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Supplementary table 1. Evidence profile of studies examining IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome Supplementary table 2. Existing systematic review on IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome Supplementary table 3. Summary tables of studies examining IV vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes) Supplementary table 4. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (categorical outcomes) Supplementary table 5. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (continuous outcomes) Supplementary table 6. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes) Supplementary table 7. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (continuous outcomes) Supplementary table 8. Evidence profile of RCTs examining CsA vs. placebo in steroid-resistant nephrotic syndrome in children Supplementary table 9. Meta-analyses and systematic reviews on steroid-resistant nephrotic syndrome in children Supplementary table 10. Evidence profile of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome Supplementary table 11. Summary table of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes) Supplementary table 12. Evidence profile of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children Supplementary table 13. Summary table of RCTs examining ACE treatment for steroid-resistant nephrotic syndrome in children (continuous outcomes) Supplementary table 14. Evidence profile of studies examining p.o. Cyc plus steroid vs. steroid in steroid-resistant nephrotic syndrome and/or FSGS in children Supplementary table 15. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (categorical outcomes) Supplementary table 16. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (continuous outcomes) Supplementary table 17. Summary table RCTs examining IV vs. p.o. Cyc treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes) Supplementary table 18. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes) Supplementary table 19. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes) Supplementary table 20. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (categorical outcomes) Supplementary table 21. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (continuous outcomes) Supplementary table 22. Evidence profile of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy Supplementary table 23. Existing systematic review on alkylating agents vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome Supplementary table 24. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (categorical outcomes) Supplementary table 25. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (continuous outcomes) Supplementary table 26. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (categorical outcomes) Supplementary table 27. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (continuous outcomes) Supplementary table 28. Evidence profile of RCTs examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy Supplementary table 29. Existing systematic reviews on CsA/TAC treatment vs. placebo for idiopathic membranous nephropathy in adults with nephrotic syndrome Supplementary table 30. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (categorical outcomes) Supplementary table 31. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (continuous outcomes) Supplementary table 32. Evidence profile of RCTs examining MMF treatment vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome Supplementary table 33. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (categorical outcomes) Supplementary table 34. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (continuous outcomes) Supplementary table 35. Evidence profile of RCTs examining alternate-day prednisone treatment vs. control in adults and children with MPGN Supplementary table 36. Summary table of studies examining alternate-day prednisone treatment vs. control in patients with MPGN (categorical outcomes) Supplementary table 37. Summary table of studies examining alternate-day prednisone treatment vs. control in patients with MPGN (continuous outcomes) Supplementary table 38. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (categorical outcomes)
Table of Contents
Supplementary table 39. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (continuous outcomes) Supplementary table 40. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (categorical outcomes) Supplementary table 41. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (continuous outcomes) Supplementary table 42. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy (categorical outcomes) Supplementary table 43. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy (continuous outcomes) Supplementary table 44. Evidence profile of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy Supplementary table 45. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 46. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 47. Evidence profile of RCTs examining steroid regimens in biopsy-proven IgA nephropathy Supplementary table 48. Meta-analyses and systematic reviews on immunosuppression for IgA nephropathy Supplementary table 49. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 50. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 51. Meta-analyses and systematic reviews on immunosuppression for IgA nephropathy Supplementary table 52. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 53. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 54. Evidence profile of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy Supplementary table 55. Summary table of RCT examining AZA in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 56. Summary table of RCT examining AZA in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 57. Evidence profile of RCTs examining MMF in biopsy-proven IgA nephropathy Supplementary table 58. Meta-analyses and systematic reviews on MMF therapy for IgA nephropathy Supplementary table 59. Summary Table of RCTs examining MMF in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 60. Summary Table of RCTs examining MMF in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 61. Evidence profile of studies examining omega-3 fatty acid treatment in IgA nephropathy Supplementary table 62. Meta-analyses and systematic reviews on fish oil treatment in IgA nephropathy Supplementary table 63. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 64. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 65. Meta-analyses and systematic reviews on antiplatelet therapy for IgA nephropathy Supplementary table 66. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 67. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 68. Summary table of RCT examining antiplatelet treatments in biopsy-proven IgA nephropathy (continuous outcomes)* Supplementary table 69. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (categorical outcomes) Supplementary table 70. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (continuous outcomes) Supplementary table 71. Evidence profile of RCTs of MMF vs. Cyc for induction therapy in lupus nephritis Supplementary table 72. Summary table of RCTs examining MMF vs. IV Cyc for induction therapy in patients with lupus nephritis (categorical outcomes) Supplementary table 73. Summary table of RCTs examining MMF vs. IV Cyc for induction therapy in patients with lupus nephritis (continuous outcomes) Supplementary table 74. Existing systematic review on Cyc vs. AZA for induction treatment in patients with lupus nephritis Supplementary table 75. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (categorical outcomes) Supplementary table 76. Summary table of RCT examining Cyc vs.AZA for induction treatment in patients with lupus nephritis (continuous outcomes) Supplementary table 77. Summary table of RCT examining low vs. high dose IV Cyc in patients with lupus nephritis (categorical outcomes) Supplementary table 78. Existing systematic review on IV vs. p.o. Cyc treatment in patients with lupus nephritis Supplementary table 79. Summary table of RCT examining IV Cyc vs. p.o. Cyc in patients with lupus nephritis (categorical outcomes) Supplementary table 80. Summary table of RCT examining Cyc vs. AZA for maintenance therapy in patients with lupus nephritis (categorical outcomes) Supplementary table 81. Summary table of RCT examining Cyc vs. AZA for maintenance therapy in patients with lupus nephritis (continuous outcomes) Supplementary table 82. Summary table of RCT examining IV Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes) Supplementary table 83. Summary table of RCT examining IV Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes) Supplementary table 84. Summary table of RCT CsA vs. IV Cyc in patients with membranous lupus nephritis (categorical outcomes) Supplementary table 85. Summary table of RCT examining rituximab + Cyc vs. rituximab in patients with proliferative lupus nephritis (categorical outcomes) Supplementary table 86. Summary table of RCT examining rituximab + Cyc vs. rituximab in patients with proliferative lupus nephritis (continuous outcomes) Supplementary table 87. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (categorical outcomes) Supplementary table 88. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (continuous outcomes) Supplementary table 89. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (categorical outcomes)
Supplementary table 90. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (continuous outcomes) Supplementary table 91. Summary table of a study examining AZA vs. IV Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes) Supplementary table 92. Summary table of a study examining MMF vs. IV Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes) Supplementary table 93. Evidence profile of studies examining MMF vs. AAZA maintenance therapy in patients with lupus nephritis Supplementary table 94.Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (categorical outcomes) Supplementary table 95. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (continuous outcomes) Supplementary table 96. Evidence profile of IV vs. p.o. Cyc for ANCA vasculitis Supplementary table 97. Existing systematic review of Induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis Supplementary table 98. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (categorical outcomes) Supplementary table 99. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (continuous outcomes) Supplementary table 100. Evidence profile of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis Supplementary table 101. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (categorical outcomes) Supplementary table 102. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (continuous outcomes)
Supplementary table 1. Evidence profile of studies examining i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Outcome Mortality ESRD Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 0 RCTs 1 Non-RCT (Moderate) 1 SR (2 RCTs) 0 RCTs 0 RCTs 0 RCTs 0 RCTs 1 Non-RCT (Moderate) 1 SR (1 RCT) Total N (treatment) --19 (10) 83 (41) ----19 (10) 48 (26) Methodological quality of studies per outcome --Some limitations (-1) Some limitations (-1) ----Some limitations (-1) Some limitations (-1) Consistency across studies --No important inconsistencies (0) ----Directness of the evidence generalizability/ applicability --Direct (0) ----Summary of findings Other considerations Quality of evidence for outcome --Sparse (-1) ------Low ----Qualitative and quantitative description of effect --Benefit for monthly i.v. cyclophosphamide at 6 but not at end of study. ----More nausea and vomiting with i.v. cyclophosphamide; more infections with p.o. cyclophosphamide. Importance of outcome Critical Critical High High High Moderate Moderate
Moderate
Balance of potential benefits and harm: No difference between monthly i.v. cyclophosphamide and oral cyclophosphamide
Supplementary table 2. Existing systematic reviews on i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome
Study, Year, RefID Hodson[34] Date Base: CENTRAL(Cochrane Renal Group), MEDLINE and EMBASE Search Dates: Central: (Sept 2007) Medline: (1966-Sept 2007) EMBASE: (1980-Sept 2007) N Studies: 26 trials included in this update N Subjects: 1173 children Study Eligibility Criteria Inclusion: 1) Children aged three months to 18 years with relapsing SSNS (i.e. the child became oedema-free and his/her urine protein was = 1+ on dipstick or <4 mg/m/h for three consecutive days while receiving corticosteroid therapy). Relapse of nephritic syndrome is defined as the recurrence of proteinuria measured semi-quantitatively on urine analysis or quantitatively using albumin or protein to creatinine ratios or timed urine specimens. A renal biopsy diagnosis of minimal change disease was not required. Exclusion: 1) First episode of SSNS 2) Steroid-resistant nephritic syndrome 3) Other renal or systemic forms of nephritic syndrome defined on renal biopsy, clinical features or serology (e.g. post-infectious glomerulonephritis, HenochSchonlein nephritis, systemic lupus erythematosus). Interventions (Studies) 1. i.v. vs. oral cyclophosphamide regimens (Abeyagunawardena 06b; Prasad 2004) Other interventions were included in the meta-analysis and are the subject of other summary tables Outcomes # children relapse within 6 months # children relapse within 1224 months Mean relapse rate/pt/y Adverse Events: HTN Leukopenia Infections Alopecia N&V/ GI Conclusions Oral or i.v. cyclophosphamide, oral chlorambucil, cyclosporin and levamisole substantially reduce the incidence of relapse in children with relapsing SSNS. The benefit of non-corticosteroid agents is sustained beyond the on-treatment period for the alkylating agents but rarely with cyclosporin and levamisole. However there are inadequate data available to determine which agent should be preferred initially. Thus the decision as to which medication should be used in a child with frequently relapsing or steroid dependent SSNS will largely depend on patient and physician preference following discussion of the possible side effects and the costs of courses of alkylating agents and those of prolonged courses of cyclosporin or levamisole. Clinically important differences in efficacy are possible and further comparative studies are still needed. Comments Is eligibility criteria similar to the guideline Yes/No Yes
No
Yes
Description of limitations of evidence by authors Author, Year, RefID Hodson 2008[34] Intervention i.v. Cyc i.v. Cyc i.v. Cyc i.v. Cyc i.v. Cyc i.v. Cyc i.v. Cyc Control p.o. Cyc p.o. Cyc p.o. Cyc p.o. Cyc p.o. Cyc p.o. Cyc p.o. Cyc
Small sample size Outcome Relapse within 6 months Continuing FRNS or SDNS at 6 months Relapse by end of study AE: All infections AE: Leukopenia AE: Hair Loss AE: Nausea & Vomiting N studies (N intervention group/ total N) 2 (41/83) 1 (26/47) 2 (41/83) 2 (41/83) 2 (41/83) 2 (41/83) 2 (41/83) Test for heterogeneity Pooled RR (95% CI) 0.54 [ 0.34, 0.88 ] 0.40 [ 0.18, 0.89 ] 0.99 [ 0.76, 1.29 ] 0.14 [ 0.03, 0.72 ] 0.37 [ 0.09, 1.51 ] 0.19 [ 0.04, 1.03 ] 4.07 [ 0.21, 80.51 ] P-value 0.01 nd 0.9 nd nd nd nd I2 Statistic (%) 0 NA 0 NA NA NA NA P-value 0.82 NA 0.86 NA NA NA NA
Supplementary table 3. Summary tables of studies examining i.v. vs. p.o. Cyc treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes)
Outcome Relapse Patients without a relapse Adverse events AE-oral thrush AE-upper respiratory infections Bircan 2003[8] Turkey 2y (12 wk) i.v. Cyc and prednisone p.o. Cyc and prednisone 10 (10) 9 (9) 0% [22%] nd nd 0% [22%] --nd nd Fair Fair Bircan 2003[8] Turkey 2y (12 wk) i.v. Cyc and prednisone p.o. Cyc and prednisone 10 (10) 9 (9) nd nd 5 (50%) [3 (33%)] RR 1.50 (0.49-4.56)1 <0.05 Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Calculated by ERT
Supplementary table 4. Summary table of RCT examining MMF vs. CsA in frequently relapsing nephrotic syndrome in children (categorical outcomes)
Outcome Relapse No relapses Adverse events AE-diarrhea AE-HTN AE-Leukopenia2 AE-hypertrichosis AE- Gingival Hyperplasia Dorresteijn 2008[21] Netherlands and Belgium 0 (0%) [0 (0%)] 1 (8%) [4 (33%)] 0 (0%) [0 (0%)] 0 (0%) [3 (38%)] 0 (0%) [6 (60%)] -0.25 (0.03-1.92) ----NS -nd nd Poor Poor Poor Poor Poor Dorresteijn 2008[21] Netherlands and Belgium 12 mo (12 mo) MMF CsA 12 (15) 12 (16) GFR 125 ml/min/1.73 m2 nd 5 (42%) [1 (8%)] 5.0 (0.68, 36.66) NS Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results No. Events (%) Intervention [Control] RR P value Quality
12 mo (12 mo)
MMF
CsA
12 (15)
12 (16)
nd
Supplementary table 5. Summary table of RCT examining MMF vs. cyclosporine in frequently relapsing nephrotic syndrome in children (continuous outcomes)
Outcome Relapse Relapse Rate Kidney function Dorresteijn 2008[21] Netherlands and Belgium 3 mo (12 mo) 6 mo (12 mo) 9 mo (12 mo) 12 mo (12 mo) -2 (-11) +1 (-16) 0 (-9) +6 (-14) Dorresteijn 2008[21] Netherlands and Belgium 12 mo (12 mo) MMF CsA 12 (15) 12 (16) GFR 125 ml/min/1.73 m2 nd per patientyear -0.83 (0.08) NS (0.08) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
GFR
MMF
CsA
12 (15)
12 (16)
nd
ml/min/ 1.73 m2
125 (123)
0.03
Poor
Supplementary table 6. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (categorical outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) Description Intervention2 Control2 No. Analyzed (Enrolled) Intervention 24 (29) Ishikura 2008[41] Japan 24 mo (24 mo) Low dose CsA Fixed dose CsA 23 (29) Control 20 (27) 19 (27) nd nd GFR/SCr Proteinuria Results Events (%) RR/OR/HR Intervention (95% CI) [Control] 50% [15%] 57% [25%] HR 0.37 (0.180.79) HR 0.43 (0.171.09) P value Quality
Sustained remission In all patients Among patients without relapse during first 6 mo 0.01 Good
NS (0.08)
Good
Biopsy results Mild arteriolar hyalinosis Ishikura 2008[41] Striped fibrosis Japan or tubular atrophy Adverse events3 AE-HTN AEhypertrichosis AE- gingival hyperplasia Ishikura 2008[41] Japan
24 mo (24 mo)
20 (29)
15 (27)
NS -NS (0.20) NS NS
Poor Poor
24 mo (24 mo)
24 (29)
20 (27)
nd
nd
2 All
Also no difference in headache, gastric pain, elevation of ALP, hyperuricemia, transient elevation of SCr. patients received 6 months of cyclosporine targeting a trough level of 80-100 ng/ml. In the subsequent 18 months, patients randomized to low dose had their dose adjusted to maintain trough cyclosporine levels 60-80 ng/mL while those randomized to fixed dose received 2.5mg/kg/day
Supplementary table 7. Summary table of RCT examining low vs. fixed dose CsA treatment in children with frequently relapsing nephrotic syndrome (continuous outcomes)
Outcome Relapse Rates Ishikura 2008[41] Japan Rate of progression to FRNS Ishikura Per patient 2008[41] year Japan Height Mean s.d. Ishikura score for 2008[41] height Japan Per patient year 24 mo (24 mo) 24 mo (24 mo) 24 mo (24 mo) Low dose CsA Low dose CsA Low dose CsA Fixed dose CsA Fixed dose CsA Fixed dose CsA 24 (29) 24 (29) 23 (29) 20 (27) 20 (27) 17 (27) nd nd -3.1 (3.6) -2.76 (-2.67) 0.14 (0.42) +0.60 (+0.58) nd Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
nd
nd
--
--
nd
Good
nd
nd
--
-0.70 (-0.62)
nd
Fair
Supplementary table 8. Evidence profile of RCTs examining CsA vs. placebo in steroid-resistant nephrotic syndrome in children
Outcome Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 0 RCTs 3 RCTs4 (High) 0 RCTs 0 RCTs 0 RCTs 0 RCTs 0 RCTs 3 RCTs6 (High) Total N (treatment) --49 (26) -----49 (26) Methodological quality of studies per outcome --No limitations5 (0) -----Consistency across studies --No important consistencies (0) -----Directness of the evidence generalizability/ applicability --Direct (0) -----Summary of findings Other considerations Quality of evidence for outcome --Sparse (-1) -------Moderate -----Qualitative and quantitative description of effect --Benefit of cyclosporine for complete remission as compared with placebo or no treatment -----No nephrotoxicity or hirsuitism reported although these are well known side effects of cyclosporine. These studies involved small numbers. Importance of outcome Critical Critical High High High High Moderate Moderate
Moderate
Balance of potential benefits and harm: Benefit of cyclosporine in inducing complete remission
One of the RCTs has only been published in abstract form (Ponticelli 1993a) but was included in the Cochrane Systematic Review (Hodson 2006[33]) The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the independent review of trials by the ERT. 6 One of the RCTs has only been published in abstract form but was included in the Cochrane Systematic Review (Ponticelli 1993a)
4 5
Supplementary table 9. Meta-analyses and systematic reviews on steroid-resistant nephrotic syndrome in children
Study, Year, RefID Hodson 2006[33] Database: Cochrane (central) Search Dates: This is an update to original search performed Cochrane (2002, issue 2) Medline 1966 April 2002 Embase 1980-April 2002 Updated with Cochrane Central Registry up to Jun 2005 N Studies: 11 N Subjects: 312 Study Eligibility Criteria Inclusion criteria Children aged three months to 18 years with corticosteroid-resistant nephrotic syndrome (i.e. persistent proteinuria >3+ on dipstick, urinary protein-creatinine ratio >0.2 g/mmol or >40 mg/m/h after four weeks or more of daily corticosteroid agent). Where a renal biopsy was performed, only children with biopsy diagnoses of MCNS, MPGN or FSGS were included. Exclusion criteria steroid-responsive nephrotic syndrome, congenital nephrotic syndrome or other renal or systemic forms of nephrotic syndrome defined on renal biopsy, clinical features or serology (e.g. post-infectious glomerulonephritis, Henoch-Schnlein nephritis, systemic lupus erythematosus, membranous glomerulopathy or mesangiocapillary glomerulonephritis) Interventions (Studies) 1) Cyclosporine vs. placebo/no treatment (Garin 1988, Lieberman 1996, Ponticelli 1993a) Outcomes 1) Complete remission during and following therapy (i.e. oedema free and urine protein was <1+ on dipstick, urine protein-creatinine <0.02 g/mmol or <4mg/m/h for three or more consecutive days). Secondary outcomes Partial remission with reduction in proteinuria (i.e. proteinuria <2+ , urine proteincreatinine ratio <0.2 g/mmol or <40 mg/m/h) and an increase in serum albumin levels. Changes in renal function (serum creatinine, creatinine clearance) Number reaching end stage renal failure Adverse effects of therapy Conclusions 1) Cyclosporine when compared with placebo or no treatment significantly increased the number who achieved complete remission Comments Is eligibility criteria similar to the guideline Are there any limitations to systematic review methodology Yes/No Yes
No
Is limitation to Yes evidence clearly addressed by the authors Trials were generally small and of variable quality. Large confidence intervals uncertainty in summary estimates. Most trials did not provide data on the duration of remission, on renal dysfunction, the number progressing to end stage renal failure or mortality. N studies (N intervention group/ total N) 3 26/49 Pooled RR1 (95% CI) Test for heterogeneity P-value I2 Statistic P-value Grading of Reference Garin 1988, Poor Lieberman 1996 Fair Ponticelli 1993a Fair
Intervention
Control
Outcome
Hodson 2006[33]
Cyclosporine
Placebo/ no treatment
Failure to achieve complete remission (all pathologies) Failure to achieve complete remission (FSGS only) Failure to achieve complete or partial remission (all pathologies) Failure to achieve complete or partial remission (FSGS)
0.012
0.82
0 77.0 NA
0.76 0.04 NA
Supplementary table 10. Evidence profile of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome
Outcome Mortality ESRD Remission # of studies and study design 0 RCTs 1 Non-RCT (Moderate) 1 RCT (High) 1 Non-RCT (Moderate) 1 Non-RCT (Moderate) 0 RCTs 0 RCTs 0 RCTs 0 RCTs 0 RCTs Total N (treatment) -14 (4) 32 (15) 14 (4) 14 (4) -----Methodological quality of studies per outcome -Serious limitations (-2) Some limitations (-1) Serious limitations (-2) Serious limitations (-2) ----Consistency across studies -NA No important inconsistencies (0) NA ----Directness of the evidence generalizability/ applicability -Direct (0) Direct (0) Direct (0) ----Summary of findings Other considerations Quality of evidence for outcome -Sparse (-1) Sparse (-1) Imprecision (-1) Sparse (-1) Imprecision (-1) -----Very low Very low -Insufficient evidence Possible benefit for CsA for remission at 12 weeks. Qualitative and quantitative description of effect Importance of outcome Critical Critical High
Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
Supplementary table 11. Summary table of studies examining CsA vs. Cyc treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes)
Outcome RRT Renal failure Remission Complete Partial Complete or Partial Complete Partial Complete or Partial Complete Partial Complete or partial Complete Partial Hafeez 2005[31] India 12 mo (12 wk) CsA Cyc 4 (4) 10 (10) nd >40 mg/m2/hr 48 wk (48 wk) 10 (15) 3 (17) Plank 2008[62] Germany, Austria 24 wk (48 wk) 13 (15) 6 (17) GFR 191 ml/min/1.73 m2 12 wk (48 wk) 15 (15) 17 (17) 2 (13%) [1 (6%)] 7 (47%) [2 (12%)] 9 (60%) [3 (18%)] 2 (15%) [1 (17%]) 9 (69%) [3 (50%)] 11 (85%) [4 (67%)] 2 (20%) [2 (67%)] 8 (80%) [1 (33%)] 10 (100%) [3 (100%)] 3 (75%) [5 (50%)] 1 (25%) [1 (10%)] RR 2.3 (0.23-23)11 nd12 nd13 RR 0.92 (0.10-8.3) 14 RR 1.38 (0.58-3.3) 15 RR 1.27 (0.69-2.3) 16 RR 0.3 (0.07-1.31) 17 RR 1.20 (0.51-2.83) 18 RR 1.00 (1.00-1.00) 19 RR 1.50 (0.65-3.47) 20 RR 2.50 (0.20-31.00) 21 NS (0.58) 0.04 0.03 NS NS NS NS NS -NS nd Fair Fair Fair Poor Poor Poor Poor Poor Poor Poor Poor Hafeez 2005[31] India 12 mo (12 wk) CsA7 Cyc8 4 (4) 10 (10) nd >40 mg/m2/hr 0 (0%) [0 (0%)] -nd Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Events (%) Intervention [Control] Results RR P value Quality
CsA9
i.v. Cyc101
217 mg/m2/h
CsA 7-10 mg/kg/d in 2 divided doses X 12 mo p.o. cyclophosphamide 2.5 mg/kg/d X 12 wk 9 Sandimmune targeting a trough level of 150 ng/mL X 12 wk and if proteinuria remained >40 mg/m2/h targeted a cyclosporine trough level of 350 ng/mL x 12 wk 10 IV Cyclophosphamide 500-1000 mg/m2 monthly X 12 wk and if proteinuria >40 mg/m2/h treated with IV MP pulses repeated monthly x 12 wk 11 Calculated by ERT 12 Not calculated since confidence intervals of calculated relative risk is not significant however, reported p values from published article show significance. This probably due to an adjusted analysis that was not described. 13 Not calculated since confidence intervals of calculated relative risk is not significant however, reported p values from published article show significance. This probably due to an adjusted analysis that was not described. 14 Calculated by ERT 15 Calculated by ERT 16 Calculated by ERT 17 Calculated by ERT 18 Calculated by ERT 19 Calculated by ERT 20 Calculated by ERT 21 Calculated by ERT
7 8
No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Events (%) Intervention [Control] 4 (100%) [5 (50%)] 1 (25%) [0 (0%)]
12 mo (12 wk)
CsA
Cyc
4 (4)
10 (10)
nd
>40 mg/m2/hr
nd
Poor
22
Calculated by ERT
Supplementary table 12. Evidence profile of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children
Outcome Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 0 RCTs 0 RCTs 0 RCTs 0 RCTs 0 RCTs 2 RCTs (High) 1 RCT (High) 0 RCTs Total N (treatment) ------95 (50) 45 (25) -Methodological quality of studies per outcome ------No limitations (0) No limitations (0) Consistency across studies ------No important consistencies (0) N/A Directness of the evidence generalizability/ applicability ------Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome ------Sparse (-1) Sparse (-1) ------Moderate Moderate Qualitative and quantitative description of effect ------Benefit of ACE-I; high dose greater than low dose greater than placebo Insufficient evidence -Importance of outcome Critical Critical High High High High Moderate Moderate Moderate
Supplementary table 13. Summary table of RCTs examining ACE-I treatment for steroid-resistant nephrotic syndrome in children (continuous outcomes)
Outcome Proteinuria 24 h Proteinuria Yi 2006[88] China 4 wk (12 wk) 12 wk (12 wk) 2-10 wk (8 wk) Fosinopril + prednisone Prednisone 25 (30) 20 (27) SCr 0.56 mg/dl 3.94 g/d g/d 3.94 (4.44) -2.69 (-1.92) -2.84 (-2.39) 34.8 (-7.9 to 76.6) Good <0.05 Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Median % reduction in UACR (low to high dose) Median % reduction in UACR (low to high Bagga dose) 2004[5] Median % India reduction in UACR (high to low dose ) Median % reduction in UACR (high to low dose) SCr/GFR/CrCl Yi 2006[88] CrCl China
nd
Good
12-20 wk (8 wk)
2-10 wk (8 wk)
37.2 (11.359.8) 25 (25) 25 (25) SCr 0.6 mg/dl UACR 3.9 % NA 62.9 (40.671.6)
nd
Good
nd
Good
12-20 wk (8 wk)
nd
Good
12 wk (12 wk)
Fosinopril + prednisone
Prednisone
25 (30)
20 (27)
3.94 g/d
ml/min/ 1.73 m2
91.3 (96.1)
-2.51 (-2.03)
NS
Good
Supplementary table 14. Evidence profile of studies of p.o. Cyc plus steroid vs. steroid in steroid-resistant nephrotic syndrome and/or FSGS in children
Outcome # of studies and study design 1 RCT (High) 2 Non-RCTs (Moderate) 2 RCTs (High) Remission 2 Non-RCTs (Moderate) 0 RCTs 0 RCTs 1 RCT (High) 1 Non-RCT (Moderate) 0 RCTs 0 RCTs 2 RCTs Adverse events 2 Non-RCTs Total N (treatment) Methodological quality of studies per outcome Some limitations23 (-1) Serious limitations24 (-2) Some limitations25 (-1) Serious limitations26 (-2) --Some limitations28 (-1) Serious limitations29 (-2) --Some limitations30 (-1) Some limitations31 (-1) Consistency across studies Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) --Direct (0) --Summary of findings Other considerations Quality of evidence for outcome Sparse (-1) Imprecision (-1) Sparse (-1) None (0) --None (0) --Very Low Qualitative and quantitative description of effect No difference Importance of outcome Critical
Mortality
60 (35) 70 (40) 93 (53) 70 (40) --60 (35) 54 (30) --93 (53) 70 (40)
N/A No important inconsistencies (0) No important inconsistencies (0) --Some inconsistencies (-1) ---
ESRD
Very Low
No difference
Critical
Moderate
No difference
High
Relapse Proteinuria (categorical) Progression of kidney disease27 Proteinuria (continuous) Kidney function (continuous)
---
---
Low
No difference
Moderate
---
Moderate
The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 25 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 26 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 27 Defined in the RCT as increase in serum creatinine from baseline of 30% or >0.4 mg/dl or onset of renal failure as evidenced by serum creatinine >4.0 mg/dl, maintenance on chronic dialysis, or renal transplantation; not defined in the NRCS 28 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 29 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 30 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials. 31 The quality of the trials is based on the evaluation performed in the systematic review (Hodson 2006), not the ERTs independent review of the trials.
23 24
Outcome
Total N (treatment)
Summary of findings Other considerations Quality of evidence for outcome Qualitative and quantitative description of effect Importance of outcome
Balance of potential benefits and harm: No difference; more adverse effects with cyclophosphamide
Supplementary table 15. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS. Based on data reported in Hodson 2006. (categorical outcomes)
Outcome Mortality 12 mo ESRD Hafeez 2005[31] India Martinelli 2004[55] Brazil Tarshish 1996[82] US ISKDC 1974[1] EU, North America Hafeez 2005[31] India Martinelli 2004[55] Brazil 12 mo (12 mo) p.o. Cyc x 12 wk p.o. steroids x 12 mo Methylprednisolone 33 >12 mo + p.o. prednisone >12 mo p.o. prednisone 10 (10) 6 (6) 0 (0%) [1 (17%)34] Tarshish 1996[82] US 12 mo (12 mo) p.o. Cyc and p.o. prednisone Prednisone 35 (35) 25 (25) GFR 118 ml/min 161 mg/m2/h 3 (9%) [2 (10%)] RR 0.98 (0.18-5.40) 32 NS (>0.1) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention [Control] RR P value Quality
12 mo
nd
>40 mg/m2/hr
--
nd
Poor
86 mo Remission Complete
p.o. Cyc and p.o. prednisone p.o. Cyc and p.o. prednisone p.o. Cyc and p.o. prednisone
nd
nd
RR0.40 (0.11-1.44) 35 RR0.88 (0.35-2.16) 36 RR 1.39 (0.66-2.93) 37 RR 1.50 (0.41-5.45)39 RR 0.60 (0.05-7.92)40 RR 2.13 (0.63-7.18) 42 RR 2.40 (0.53-10.84) 44
Poor
Prednisone
161 mg/m2/hr
Fair
>40 mg/m2/h
Fair
12 mo (12 mo)
10 (10)
6 (6)
nd
>40 mg/m2/hr
Poor
86 mo (4 mo)
30 (30)
24 (24)
Poor Poor
nd
nd
Calculated by ERT Some converted partially or fully to oral steroids. Cyclophosphamide added if response was not satisfactory. 34 Showed no response to therapy. Had FSGS. Developed renal failure over a period of 1 year. 35 Calculated by ERT 36 Calculated by ERT 37 Calculated by ERT 38 Some converted partially or fully to oral steroids. Cyclophosphamide added if response was not satisfactory. 39 Calculated by ERT 40 Calculated by ERT 41 The data reported in the article appear to be for combined (Prednisone alone) + (Cyc + Pred). These numbers are derived from subtracting (Cyc + Pred) from Prednisone. 42 Calculated by ERT
32 33
Outcome
RR
P value
Quality
p.o. Cyc and p.o. prednisone p.o. Cyc and p.o. prednisone
35 (35) 30 (30)
25 (25) 24 (24)
161 mg/m2/hr nd
NS (>0.1) NS
Fair Poor
The data reported in the article appear to be for combined (Prednisone alone) + (Cyc + Pred). These numbers are derived from subtracting (Cyc + Pred) from Prednisone. Calculated by ERT 45 Calculated by ERT 46 Calculated by ERT 16 Defined as increase in serum creatinine from baseline of 30% or >0.4 mg/dl or onset of renal failure as evidenced by serum creatinine >4.0 mg/dl, maintenance on chronic dialysis, or renal transplantation.
43 44
Supplementary table 16. Summary table of studies examining p.o. Cyc plus steroid vs. steroid in children with SRNS or FSGS (continuous outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) 2y (90 d) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) 38.4 (95.5) P value Quality
p.o. Cyc
Prednisone
18 (18)
15 (15)
nd
nd
NA
<0.05
Fair
Supplementary table 17. Summary table RCT examining i.v. vs. p.o. Cyc treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes)
Outcome Proteinuria Median UPCR SCr/GFR/CrCl Median GFR Mantan 2008[54] India 6 mo (18 mo) 6 mo (18 mo) i.v. Cyc p.o. Cyc 26 (27) 26 (27) 23 (25) 23 (25) GFR 101 ml/min/1.73 m2 GFR 101 ml/min/1.73 m2 UPCR 5.9 mg/mg UPCR 5.9 mg/mg ml/min/1. 73 m2 101 (107) 2.2 (1.7) +2 (0) +1.8 (+1.9) NS (0.2) NS (0.7) Poor Mantan 2008[54] India 6mo (18 mo) i.v. Cyc p.o. Cyc 26 (27) 23 (25) GFR 101 ml/min/1.73 m2 UPCR 5.9 mg/mg mg/mg 5.9 (8.9) -4.3 (-4.4) NS (0.2) Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
i.v. Cyc
p.o. Cyc
g/dl
Poor
Supplementary table 18. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (categorical outcomes)
Outcome Remission Complete remission Partial remission Complete or partial remission Complete remission Partial remission Complete or partial remission Relapse after achieving remission Nephrotoxicity Persistent Reversible Adverse Events AE-worsening of HTN AE-hypertrichosis AE-gingival hyperplasia AE-diarrhea AE-sepsis/ pneumonia AE-headache AE-paresthesia Choudhry 2009[14] India GFR 105 ml/min SCr 0.56 mg/dl Choudhry 2009[14] India 6 mo (12 mo) Choudhry 2009[14] India 12 mo (12 mo) GFR 105 ml/min SCr 0.56 mg/dl Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention [Control] 43% [50%] 43% [30%] 86% [80%] 48% [55%] 38% [20%] 86% [75%] 11% [50%] GFR 105 ml/min SCr 0.56 mg/dl 5% [10%] 33% [50%] 10% [0%] 0% [95%] 5% [60%] 29% [5%] 5% [5%] 0% [5%] 0% [5%] RR P value Quality
Tacrolimus
CsA
21 (21)
20 (20)
0.85 (0.44-1.65) 1.42 (0.62-3.2) 1.07 (0.81-1.41) 0.86 (0.47-1.57) 1.90 (0.67-5.34) 1.14 (0.84-1.55) 0.22 (0.06-0.90) 0.48 (0.05-4.9) 0.67 (0.32-1.41) 0.89 (0.14-5.6) -0.07 (0.01-0.51) 5.3 (0.72-40) 0.89 (0.06-13) ---
NS (0.6) NS (0.4) NS (0.6) NS (0.6) NS (0.2) NS (0.4) 0.03 NS (0.5) NS (0.3) NS (0.9) <0.001 <0.001 NS NS (0.9) NS (0.3) NS (0.3)
12 mo (12 mo)
Tacrolimus
CsA
21 (21)
20 (20)
12 mo (12 mo)
Tacrolimus
CsA
18 (21)
16 (20)
Supplementary table 19. Summary table of RCT examining TAC vs. CsA treatment in children with steroid-resistant nephrotic syndrome (continuous outcomes)
Outcome Proteinuria UPCR Scr/GFR/CrCl 12 mo Schwartz GFR Albumin 12 mo Choudhry 2009 [14] India 12 mo (12 mo) Tacrolimus CsA 19 (21) 16 (20) GFR 105 ml/min SCr 0.56 mg/dl UPCR 9.8 g/g g/dl 1.8 (1.6) +2.6 (+2.3) NS (0.08) Fair Choudhry 2009[14] India 12 mo (12 mo) Tacrolimus CsA 19 (21) 16 (20) GFR 105 ml/min SCr 0.56 mg/dl g/dl UPCR 9.8 g/g ml/min/1. 73 m2 0.56 (0.51) 104.6 (115.5) +0.12 (+0.12) -14.4 (-12%) [-16.2 (-11%) ] NS (0.3) NS (0.1) Fair Fair Choudhry 2009[14] India 12 mo (12 mo) Tacrolimus CsA 19 (21) 16 (20) GFR 105 ml/min SCr 0.56 mg/dl UPCR 9.8 g/g g/g 9.8 (8.0) -9.3 (-7.4) NS (0.8) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 20. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (categorical outcomes)
Outcome Remission 2 wk (6 mo) 4 wk (6 mo) 3 mo (6 mo) 6 mo (6 mo) 2 wk (6 mo) 4 wk (6 mo) 3 mo (6 mo) 6 mo (6 mo) 20 (77%) [11 (42%)] 25 (96%) [20 (77%)] 24 (92%) [24 (92%)] 21 (81%) [20 (77%)] 0 (0%) [0 (0%)] 0 (0%) [1 (4%)] 2 (8%) [2 (8%)] 5 (19%) [6 (23%)] RR 1.8247 (1.11-2.99) RR 1.2548 (1.00-1.56) RR 1.0049 (0.85-1.17) RR 1.0550 (0.79-1.39) --RR 1.0051 (0.15-6.57) RR 0.8352 (0.29-2.39) 0.02 nd Fair nd nd nd nd Fair nd nd Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention [Control] RR P value Quality
Complete remission
CsA + prednisolone
Prednisolone
26 (26)
26 (26)
6.7 g/d
Relapse
Relapse
CsA + prednisolone
Prednisolone
26 (26)
26 (26)
6.7 g/d
Calculated by ERT Calculated by ERT 49 Calculated by ERT 50 Calculated by ERT 51 Calculated by ERT 52 Calculated by ERT
47 48
Supplementary table 21. Summary table of RCT examining CsA vs. steroid treatment after first relapse in adults with minimal change disease (continuous outcomes)
Outcome Proteinuria 2 wk (6 mo) 4 wk (6 mo) 3 mo (6 mo) 6 mo (6 mo) -5.9 (-5.1) -6.4 (-6.5) -6.2 (-6.7) -5.8 (-6.4) <0.05 NS (0.1) NS (0.9) NS (0.7) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Proteinuria
CsA + prednisolone
Prednisolone
26 (26)
26 (26)
6.7 g/d
g/d
6.4 (6.9)
Supplementary table 22. Evidence profile of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy
Outcome # of studies and study design 2 RCT (High) 1 SR (4 trials) 2 RCT (High) 1 SR (4 trials) 2 RCT (High) 1 SR (4 trials) 2 RCT (High) 1 RCT (High) 1 RCT (High) 1 RCTs (High) 1 RCTs (High) 2 RCTs Adverse events 1 SR (4 trials) Total N (treatment) 174 (89) 196 (103) 174 (89) 196 (103) 174 (89) 176 (94) 174 (89) 81 (42) 81 (42) 93 (47) 93 (47) 174 (89) 196 (103) Methodological quality of studies per outcome Some limitations (-1) No limitations (0) Some limitations (-1) No limitations (0) Some limitations (-1) No limitations (0) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Consistency across studies No important consistencies (0) No important consistencies (0) No important inconsistencies (0) No important inconsistencies (0) NA NA NA NA Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) Direct (0) Direct (0) Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome Imprecision (-1) Imprecision (-1) None (0) None (0) Sparse (-1) Sparse (-1) Sparse (-1) Sparse (-1) Qualitative and quantitative description of effect Importance of outcome
Mortality
Low
Insufficient evidence
Critical
ESRD
Low
Critical
Remission
Moderate
High
Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous)
Benefit for alkylating agents plus steroids Harm for alkylating agents plus steroids Possible benefit for alkylating agents plus steroids Possible benefit for alkylating agents plus steroids No difference Higher incidence of patient discontinuation due to adverse events for alkylating agents plus steroids.
Moderate
Balance of potential benefits and harm: Benefit of alkylating agents plus steroids
Supplementary table 23. Existing systematic reviews on alkylating agents vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome
Study, Year, RefID Schieppati 2004[71] Date Base: Cochrane Renal, Cochrane CENTRAL, MEDLINE, PreMEDLINE, EMBASE Search Dates: 1966-2003 Study Eligibility Criteria Interventions (Studies) The following classes of immunosuppressive treatments were considered: glucocorticoids (alone) alkylating agents (alone or in association with glucocorticoids) calcineurin inhibitors (alone or in association with glucocorticoids) anti-proliferative agents (alone) Control groups were given placebo or no treatment in addition to supportive therapy. Outcomes Definite endpoints death ESRF which requires the initiation of dialysis or kidney transplantation. Surrogate endpoints Partial remission Complete remission Final proteinuria, measured as g/24 h Final serum creatinine, measured as mol/L Final GFR, measured as ml/min/1.73 m2. The following outcome measures for safety were evaluated: Side effects Proportion of patients experiencing any side effect leading to patient withdrawal. Side effects might include, but are not limited to, leukopaenia, cushingoid features, gastric disorders. Conclusions This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil. Comments Is eligibility criteria similar to the guideline Yes/No Yes
Randomized controlled trials and quasiRCTs comparing any immunosuppressive interventions for the treatment of IMN in adults. Inclusion criteria The selected patients were adult subjects with IMN, aged 16 years or older, with nephrotic syndrome. The diagnosis of IMN was histologically proven. The assessment of nephrotic syndrome relies on that chosen by the authors in the single studies. It must be N Studies: 18 said that this definition can be heterogeneous. In trials that included a minority of non-nephrotic subjects, when possible, analyses will be N Subjects: 1025 restricted to nephrotic patients only. In absence of an explicit definition of nephrotic syndrome, the cut-off point of urinary protein excretion above 3.5 g/24 h was used. Description of limitations of evidence by authors
No
No
Intervention Alkylating agents Alkylating agents Alkylating agents Alkylating agents Alkylating agents Alkylating agents Alkylating agents Alkylating agents
Outcome Death ESRD ESRD or Death Final proteinuria Partial remission Complete remission Complete or partial remission Final SCr
N studies (N intervention group/ total N) 4 (103/196) 4 (103/196) 4 (103/96) 4 (103/196) 4 (94/176) 4 (94/176) 4 (94/176) 2 (55/107)
Test for heterogeneity Pooled RR1(95% CI) 0.94 (0.14-6.22) 0.44 (0.11-1.80) 0.56 (0.18-1.70) -2.36 (-4.27, -0.46) 1.22 2.37 (1.32-4.25) 1.55 (0.72-3.34) -38.37 (-117.67, 100.93) P-value 1 0.30 0.30 0.02 0.60 0.004 0.30 0.60 I2 Statistic 0.0% 0.0% 0.0% 35.8% 50.1% 0.0% 79.9% 87.4% P-value 0.33 0.44 0.40 0.21 0.11 0.37 0.002 0.005
Test for heterogeneity Pooled RR1(95% CI) 1.00 (-18.86, 20.86) 5.97 (1.08-32.86) P-value 0.90 0.04 I2 Statistic N/A 0.0% P-value N/A 0.90
Supplementary table 24. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (categorical outcomes)
Outcome Mortality Jha 2007[42] India Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents Symptomatic therapy with dietary sodium restriction, diuretics and anti-HTN agents Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents Symptomatic therapy with dietary sodium restriction, diuretics and anti-HTN agents Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents SCr 1.21 mg/dl GFR 89 ml/min Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Death
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
1 (2%) [3 (7%)]
nd
Good
Death
10 y (6 mo)
42 (42)
39 (39)
1 (2%) [3 (8%)]
nd
Fair
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
89% [65%]
--
0.016
Good
RRT Cumulative probability of being alive with functioning kidney at 10 y Remission Complete remission Partial remission Ponticelli 1995[63] Italy 10 y (6 mo) Methylprednisolone and chlorambucil
2 (5%) [9 (23%)] 42 (42) 39 (39) SCr 93.8 mol/L UPE 6.18 g/d 0.92 (0.83-1.00) [0.60 (0.42-0.78)]
nd
Fair
0.0038
Fair
10 y (6 mo)
47 (51)
46 (53)
<0.0001
Good
<0.0001
Good
aaa bbb
Calculated by ERT Calculated by ERT ccc Calculated by ERT ddd Calculated by ERT eee Calculated by ERT
Description Intervention Control Symptomatic therapy with dietary sodium restriction, diuretics and anti-HTN agents Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents Symptomatic therapy Supportive therapy of low salt diet, diuretics and anti-HTN medication Supportive therapy of low salt diet, diuretics and anti-HTN medication Supportive therapy with dietary sodium restriction,
Results Events (%) Intervention RR/OR/HR [Control] 35 (83%) [15 (38%)] RR 2.17 (1.42-3.30) fff RR 7.89 (1.95-31.97) ggg RR 0.76 (0.35-1.63) hhh
P value
Quality
nd nd nd
10 y (6 mo)
42 (42)
39 (39)
Relapse
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
4 of 34 (12%) [8 of 16 (9%)]
nd
Good
Relapse Proteinuria Patients with nephrotic syndrome at last follow-up Kidney function
10 y (6 mo)
42 (42)
39 (39)
4 of 35 (10%) [nd]
--
nd
Poor
10 y (6 mo)
42 (42)
39 (39)
9 (21%) [6 (15%)]
nd
Fair
SCr 50%
10 y (6 mo)
42 (42)
39 (39)
4 (10%) [8 (21%)]
nd
Fair
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
NS (0.35) nd
Good Good
Calculated by ERT Calculated by ERT hhh Calculated by ERT iii Calculated by ERT jjj Calculated by ERT kkk Calculated by ERT lll Calculated by ERT mmm Calculated by ERT
ggg
Outcome
Results Events (%) Intervention RR/OR/HR [Control] 0 (0%) [0 (0%)] 4 (10%) [nd] -------
P value
Quality
AE-malignancy D/C due to AE in treatment group AE-moderate leukopenia AE-tremors AE-cramps AE-anxiety
nd nd nd nd nd nd
10 y (6 mo)
42 (42)
39 (39)
Supplementary table 25. Summary table of RCTs examining alkylating agents plus steroid treatment vs. control in patients with membranous nephropathy (continuous outcomes)
Outcome Proteinuria Jha 2007[42] India Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents Supportive therapy with dietary sodium restriction, diuretics and anti-HTN agents Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Proteinuriannn
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
g/d
6.11 (5.91)
-5.21 (-3.31)
nd
Fair
MDRD eGFRooo
10 y (6 mo)
47 (51)
46 (53)
6.11 g/d
ml/min
89 (84)
-27 (-32)
nd
Fair
nnn ooo
Supplementary table 26. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (categorical outcomes)
Outcome Remission Remission Complete remission Partial remission Adverse Events AE-leukopenia AE-dizziness AE-glucose intolerance AE-diarrhea AEonycodystrophy AE-folliculitis AE-bronzing of skin Ponticelli 2006[64] Italy Methlyprednisolone and chlorambucil or Cyc Ponticelli 2006[64] Italy 12 mo (6 mo) Methlyprednisolone and chlorambucil or Cyc Tetracosactide (ACTH) 16 (16) 16 (16) SCr 0.9 mg/dl 5.5 g/d 15 (93%) [14 (87%)] 5 (31%) [10 (63%)] 10 (63%) [4 (25%)] 1 (6%) [0 (0%)] 0 (0%) [1 (6%)] 2 (13%) [2 (13%)] 0 (0%) [1 (6%)] 0 (0%) [1 (6%)] 0 (0%) [1 (6%)] 0 (0%) [1 (6%)] RR 1.07 (0.86-1.34)68 RR 0.50 (0.22-1.14) 69 RR 2.50 (0.99-6.33) 70 -------NS NS NS nd nd nd nd nd nd nd Poor Poor Poor Poor Poor Poor Poor Poor Poor Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
12 mo (6 mo)
Tetracosactide (ACTH)
16 (16)
16 (16)
5.5 g/d
Supplementary table 27. Summary table of RCTs examining alkylating agents plus steroid treatment vs. ACTH in patients with membranous nephropathy (continuous outcomes)
Outcome Proteinuria Median SCr/GFR/CrCl Median SCr Ponticelli 2006[64] Italy 12 mo (6 mo) Methlyprednisolone Tetracosactide (ACTH) 16 (16) 16 (16) SCr 0.9 mg/dl 5.5 g/d mg/dl 0.9 (0.9) +0.1 (+0.1) NS Poor Ponticelli 2006[64] Italy 12 mo (6 mo) Methlyprednisolone Tetracosactide (ACTH) 16 (16) 16 (16) SCr 0.9 mg/dl 5.5 g/d g/d 5.1 (6.0) -3.0 (-5.7) NS Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 28. Evidence profile of RCTs examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy
Outcome # of studies and study design 1 SR (3 RCTs) 1 SR (3 RCTs) 1 RCT (High) 1 SR (2 RCTs) 0 RCTs 0 RCTs 1 RCT (High) 1 RCT (High) 0 RCTs 1 RCT Adverse events 1 SR (3 RCTs) Total N (treatment) 104 (63) 104 (63) 48 (25) 104 (63) --48 (25) 48 (25) -48 (25) 104 (63) Methodological quality of studies per outcome Some limitation (-1) Some limitation (-1) No limitations (0) Some limitation (-1) --No limitations (0) No limitations (0) -Consistency across studies No important inconsistencies (0) No important inconsistencies (0) Important inconsistencies (-1) --N/A No important inconsistencies (0) -Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) --Direct (0) Direct (0) -Summary of findings Other considerations Quality of evidence for Qualitative and quantitative description outcome of effect Imprecision (-1) Imprecision (-1) None (0) --Sparse (-1) Sparse (-1) -Low Low Insufficient evidence Insufficient evidence Benefit for tacrolimus in one RCT. No difference for cyclosporine. --Benefit for tacrolimus Benefit for tacrolimus. -Possible increase in glucose intolerance with tacrolimus. Importance of outcome Critical Critical
Mortality ESRD
Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous)
Moderate
Balance of potential benefits and harm: Benefit for tacrolimus. No difference for cyclosporine.
Supplementary table 29. Existing systematic reviews on CsA/TAC treatment vs. placebo for idiopathic membranous nephropathy in adults with nephrotic syndrome
Study, Year, RefID Schieppati 2004[71] Date Base: Cochrane Renal, Cochrane CENTRAL, MEDLINE, PreMEDLINE, EMBASE Search Dates: 1966-2003 Study Eligibility Criteria Interventions (Studies) The following classes of immunosuppressive treatments were considered: glucocorticoids (alone) alkylating agents (alone or in association with glucocorticoids) calcineurin inhibitors (alone or in association with glucocorticoids) anti-proliferative agents (alone) Control groups were given placebo or no treatment in addition to supportive therapy. Outcomes Definite endpoints death ESRF which requires the initiation of dialysis or kidney transplantation. Surrogate endpoints Partial remission Complete remission Final proteinuria, measured as g/24 h Final serum creatinine, measured as mol/L Final GFR, measured as ml/min/1.73 m2. The following outcome measures for safety were evaluated: Side effects Proportion of patients experiencing any side effect leading to patient withdrawal. Side effects might include, but are not limited to, leukopaenia, cushingoid features, gastric disorders. Conclusions This review failed to show any long-term effect of immunosuppressive treatment on patient and/or renal survival. There was an increased number of discontinuations due to adverse events in immunosuppressive treatment groups. Within the class of alkylating agents there is weak evidence supporting the efficacy of cyclophosphamide as compared to chlorambucil. On the other hand, cyclophosphamide had fewer side effects leading to patient withdrawal than chlorambucil. Comments Is eligibility criteria similar to the guideline Yes/No Yes
Randomized controlled trials and quasi-RCTs comparing any immunosuppressive interventions for the treatment of IMN in adults. Inclusion criteria The selected patients were adult subjects with IMN, aged 16 years or older, with nephrotic syndrome. The diagnosis of IMN was histologically proven. The assessment of nephrotic syndrome relies on that chosen by the authors in the single studies. It N Studies: 18 must be said that this definition can be heterogeneous. In trials that included a minority of non-nephrotic N Subjects: 1025 subjects, when possible, analyses will be restricted to nephrotic patients only. In absence of an explicit definition of nephrotic syndrome, the cut-off point of urinary protein excretion above 3.5 g/24 h was used. Description of limitations of evidence by authors Author, Year, RefID Schieppati 2004[71] Study Years : 1966-2003 Declining renal function at baseline: No: 1 study Yes: 2 studies Use of ACE-I during follow-up: Yes, confounding effect: 2 studies No confounding effect: 1 study Mean follow-up: 12, 15, and 21 mo Grading: 2 A and 1 B Intervention CsA CsA CsA
No
No
Outcome Death ESRD ESRD or Death Final proteinuria Partial remission Complete remission Complete or partial remission
N studies (N intervention group/ total N) 3 (63/104) 3 (63/104) 3 (63/104) 2 (19/38) 2 (54/87) 2 (54/87) 2 (54/87)
Pooled RR71 (95% CI) 2.70 (0.13-58.24) 0.88 (0.21-3.66) 0.93 (0.32-2.71) WMD72 -0.08 (-9.29, 9.13) 1.08 (0.76-1.55) 1.10 (0.41-2.96) 1.00 (0.72-1.40)
Test for heterogeneity P-value I2 Statistic N/A 42% 20% 87% 0% 0% 0% N/A 0.18 0.29 0.005 0.60 0.46 0.39
71 72
CsA Placebo CsA Placebo CsA Placebo Final GFR D/C due to AEs Final SCr
WMD 11.50 (-50.19, 73.19) WMD 8.31 (-10.83, 27.45) 5.45 (0.29-101.55)
Supplementary table 30. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (categorical outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) 2 mo (18 mo) 6 mo (18 mo) 12 mo (18 mo) 18 mo (18 mo) 6 mo (18 mo) 12 mo (18 mo) 18 mo (18 mo) 18 mo (18 mo) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] 9 (36%) [2 (9%)] 14 (56%) [3 (13%)] 18 (72%) [5 (22%)] 19 (76%) [6 (30%)] 58% [10%] 82% [24%] 94% [35%] 6.1 [11.3] RR 4.14 (1.00-17.19) 73 RR 4.29 (1.41-13.04) 74 RR 3.31 (1.47-7.47) 75 RR 2.91 (1.41-6.00) 76 ---<0.00001 P value Quality
Remission (PR or CR) 2 mo 6 mo 12 mo 18 mo Probability of PR or CR 6 mo 12 mo 18 mo Mean time to PR or CR Mean time (mo) Praga 2007[69] Spain Praga 2007[69] Spain Tac Control 25 (25) 23 (23) SCr 0.98 mg/dl GFR 104 ml/min SCr 0.98 mg/dl GFR 104 ml/min 7.2 g/d -0.003 Good Praga 2007[69] Spain 25 (25) 23 (23) SCr 0.98 mg/dl GFR 104 ml/min Good Good Good Praga 2007[69] Spain <0.04 <0.01 <0.001 0.003 Good Good Good Good SCr 0.98 mg/dl GFR 104 ml/min
Tac
Control
25 (25)
23 (23)
7.2 g/d
Tac
Control
7.2 g/d
Kidney function SCr 50% 18 mo (18 mo) Tac Control 25 (25) 23 (23) 7.2 g/d 1 (4%) [6 (26%)] 4 (16%) [2 (9%)] 0 (0%) [2 (9%)] 2 (8%) [0 (0%)] 1 (4%) [0 (0%]) 0 (0%) [1 (4%)] RR 0.15 (0.02-1.18) 77 RR 1.84 (0.37-9.12) 78 ----0.03 Good
Adverse Events AE-glucose intolerance AE-chest pain Praga AE-diarrhea 2007[69] Spain AE- gouty arthritis AE- UTI
nd nd nd nd nd
18 mo (18 mo)
Tac
Control
25 (25)
23 (23)
7.2 g/d
73 74
Calculated by ERT Calculated by ERT 75 Calculated by ERT 76 Calculated by ERT 77 Calculated by ERT 78 Calculated by ERT
Results Events (%) Intervention RR/OR/HR [Control] 1 (4%) -[0 (0%]) 1 (4%) -[0 (0%]) 1 (4%) -[0 (0%])
P value nd nd nd
Supplementary table 31. Summary table of RCT examining CsA/TAC treatment vs. control for idiopathic membranous nephropathy (continuous outcomes)
Outcome Proteinuria 12 mo 18 mo Praga 2007[69] Spain 12 mo (18 mo) Tac Control 25 (25) 23 (23) SCr 0.98 mg/dl GFR 104 ml/min 7.2 (8.4) 7.2 g/d g/d 7.2 (8.4) -5.6 (-4.3) -5.3 (-5.2) 0.045 0.048 Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 32. Evidence profile of RCTs examining MMF treatment vs. control for idiopathic membranous nephropathy in adults with nephrotic syndrome
Outcome Mortality ESRD Remission # of studies and study design 0 RCTs 0 RCTs 3 RCTs (High) 2 RCT (High) 0 RCTs 2 RCT (High) 3 RCTs (High) 2 RCT (High) 2 RCT Total N (treatment) --73 (37) 41 (22) -52 (26) 73 (37) 41 (22) 52 (26) Methodological quality of studies per outcome --Some limitations (-1) Some limitations (-1) -Some limitations (-1) Some limitations (-1) Some limitations (-1) Consistency across studies --No important inconsistencies (0) Important inconsistencies (-1) -Important inconsistencies (-1) Important inconsistencies (0) No important inconsistencies (-1) Directness of the evidence generalizability/ applicability --Direct (0) Direct (0) -Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome --Sparse (-1) Imprecision (-1) Sparse (-1) Imprecision (-1) -Sparse (-1) Imprecision (-1) Sparse (-1) Sparse (-1) --Very low --Insufficient evidence Qualitative and quantitative description of effect Importance of outcome Critical Critical High
Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
Low Low
No difference No difference Higher incidence of adverse events and serious adverse events with MMF
Supplementary table 33. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (categorical outcomes)
Outcome Remission Complete remission Partial remission Complete remission Partial remission Remissions Complete remission Partial remission Composite endpoint of CR or PR Time to remission (mo) Complete remission Partial remission Time to remission (wk) Relapse or Failure Treatment failure Relapse Relapse in CR or PR (n=13) Relapse Chan 2007[11] China Nayagam 2008[59] India Calculated by ERT Calculated by ERT 81 Calculated by ERT 82 Calculated by ERT 83 Calculated by ERT 84 Calculated by ERT
79 80
Description Intervention Control Conservative treatment with ACE-I, statins, low-salt and lowprotein diet, and loop diuretic Conservative treatment with ACE-I, statins, low-salt and lowprotein diet, and loop diuretic
P value
Quality
15 (19)
17 (17)
SCr 1.01 mg/dl GFR 92 ml/min SCr 1.01 mg/dl GFR 92 ml/min
Fair Fair Fair Fair Fair Fair Fair Fair Fair Good Good Good Fair Fair Fair Good
6.2 g/d
4 (27%) [3 (18%)] 1 (6%) [2 (12%)] 6 (40%) [5 (29%)) 37% [41%] 3 (27%) [3 (33%)] 4 (36%) [3 (33%)] 64% [68%] 5 [6] 5 (45%) [3 (30%)] 2 (18%) [5 (50%)] 9.2 [10.4] 4 (36%) [3 (33%)] 2 (18%) [1 (11%)] 3 (23%) 0 (0%) [1 (10%)]
15 (19)
17 (17)
6.2 g/d
RR 0.92 (0.48-1.75) -RR 0.82 (0.22-3.11) 79 RR 1.09 (0.33-3.66) 80 --RR 1.52 (0.48-4.77) 81 RR 0.36 (0.09-1.47) 82 -RR 1.09 (0.33-3.66) 83 RR 2.27 (0.23-22.56) 84 ---
15 mo (6 mo)
11 (11)
9 (9)
100 mol/L
5.7 g/d
12 mo (6 mo)
11 (11)
10 (10)
GFR 86 ml/min
15 mo (6 mo) 12 mo (6 mo)
11 (11) 11 (11)
9 (9) 10 (10)
100 mol/L
5.7 g/d
GFR 86 ml/min
Outcome
No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria (MN and FSGS)
P value
Quality
Kidney Function Dussol 2008[22] France Chan 2007[11] China 12 mo (12 mo) MMF and conservative treatment Conservative treatment with ACE-I, statins, low-salt and lowprotein diet, and loop diuretic Modified Ponticelli regimen 15 (19) 17 (17) SCr 1.01 mg/dl GFR 92 ml/min 0 (0%) [0 (0%)] 2 (18%) [0 (0%)] 3 (27%) [1 (11%)] 3 (20%) [0 (0%)] 4 (27%) [5 (29%)] 2 (13%) [1 (6%)] 2 (13%) [1 (6%)] 1 (7%) [1 (6%)] 1 (7%) [2 (12%)] 0 (0%) [1 (6%)] 1 (7%) [0 (0%)] 3 (27%) [2 (22%)] 6 (30%) 1 (9%) [1 (11%)]
SCr 20%
6.2 g/d
--
nd
Fair
15% SCr 15% SCr Adverse Events Serious AEs AE-muscular pain AE-anemia AEnausea/vomiting AE-hypotension AE-cough AE-acute bronchitis AE-cytolysis AE-infection AE-leucopenia AE-new onset DM
85 86
15 mo (6 mo)
11 (11)
9 (9)
-2.45 (0.31-19.74) 85 -RR 0.91 (0.30-2.71) 86 RR 2.27 (0.23-22.56) 87 RR 2.27 (0.23-22.56) 88 RR 1.13 (0.08-16.59) 89 RR 0.57 (0.06-5.64) 90 --RR 1.23 (0.26-5.82) 91 -RR 0.82 (0.06-11.33) 92
nd nd nd nd nd nd nd nd nd nd nd nd nd
Poor Poor Fair Fair Fair Fair Fair Fair Fair Fair Poor Poor Poor
100 mol/L
5.7 g/d
12 mo (12 mo)
Conservative treatment with ACE-I, statins, low-salt and lowprotein diet, and loop diuretic
15 (19)
17 (17)
6.2 g/d
15 mo (6 mo)
11 (11)
9 (9)
100 mol/L
5.7 g/d
Calculated by ERT Calculated by ERT 87 Calculated by ERT 88 Calculated by ERT 89 Calculated by ERT 90 Calculated by ERT 91 Calculated by ERT 92 Calculated by ERT
Outcome AE-death
P value nd
Quality Poor
Supplementary table 34. Summary table of RCTs examining MMF treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome (continuous outcomes)
Outcome Proteinuria Dussol 2008[22] France Chan 2007[11] China Nayagam 2008[59] India 12 mo (12 mo) MMF and conservative treatment MMF and prednisone MMF and prednisone Conservative treatment with ACE-I, statins, lowsalt and low-protein diet, and loop diuretic Modified Ponticelli regimen Conventional therapy with methlyprednisolone and p.o. prednisone Modified Ponticelli regimen Conventional therapy with methlyprednisolone and p.o. prednisone 15 (19) 17 (17) SCr 1.01 mg/dl GFR 92 ml/min 100 mol/L GFR 86 ml/min 4865 (6548) +213.07 (-1834.6) Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention Intervention (Control) (Control) P value Quality
Mean UPCR
6.2 g/d
nd
0.3
Fair
Proteinuria
15 mo (6 mo) 12 mo (6 mo)
11 (11) 11 (11)
9 (9) 10 (10)
g/d
nd
Poor
mg/mg
nd
Fair
15 mo (6 mo)
11 (11)
9 (9)
100 mol/L
nd nd
Poor Poor
MDRD GFR
12 mo (6 mo)
11 (11)
10 (10)
GFR 86 ml/min
ml/min
nd
Good
Supplementary table 35. Evidence profile of RCTs examining alternate-day prednisone treatment vs. control in adults and children with MPGN
Outcome # of studies and study design 1 RCT (High) 1 RCT (High) 1 RCT (High) 0 RCTs 0 RCTs 2 RCTs (High) 1 RCT (High) 1 RCT (High) 1 RCT (High) Total N (treatment) 77 (44) 18 (8) 18 (8) --95 (52) 18 (8) 18 (8) 77 (44) Methodological quality of studies per outcome Serious limitations (-2) Some limitations (-1) Some limitations (-1) --Some limitations (-1) Serious limitations (-2) Serious limitations (-2) Consistency across studies Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) --Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome Sparse (-1) Sparse (-1) Imprecision (-1) Sparse (-1) Imprecision (-1) --Sparse (-1) Sparse (-1) Sparse (-1) Very low Qualitative and quantitative description of effect No difference Importance of outcome Critical
Mortality
N/A
ESRD
N/A
Very low
Critical
Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
Insufficient evidence --Possible benefit with prednisone in Type I and III Possible benefit with prednisone Benefit with prednisone Higher incidence of hypertensive encephalopathy and steroid toxicity with prednisone.
Supplementary table 36. Summary table of RCTs examining alternate-day prednisone treatment vs. control in patients with MPGN (categorical outcomes)
Outcome Mortality Death ESRD ESRD Remission 1, 2, or 8 y Kidney Function Moderate increase in SCr MotaHernandez 1985[58] Mexico 5y (nd) 63 mo (41 mo) SCr 30% or 0.4 mg/dl (35 mol/L) 130 mo (survival analysis) Alternate-day prednisone 63 mo (41 mo) SCr4.0 mg/dl (350 mol/L) Adverse Events Placebo Alternate-day prednisone Lactose 8 (8) 10 (10) SCr 0.78 mg/dl 99 mg/h/m2 3 (38%) [0 (0%)] 16 (36%) [18 (55%)] 59% [88%] GFR 112 ml/min/1.73 m2 (62 mol/L) 122 mg/h/m2 9 (29%) [15 (58%)] 5 (56%) [3 (60%)] 13 (30%) [14 (42%)] -RR 0.67 (0.40-1.10)
95
Study, Year Country Tarshish 1992[81] US, Europe, Mexico MotaHernandez 1985[58] Mexico MotaHernandez 1985[58] Mexico
Results Events (%) Intervention RR/OR/HR [Control] 2 (5%) [4 (12%)] RR 0.38 (0.07-1.93)
93
P value
Quality
Alternate-day prednisone
Placebo
44 (47)
33 (33)
122 mg/h/m2
0.240
Poor
2-5 y (nd)
Alternate-day prednisone
Lactose
8 (8)
10 (10)
99 mg/h/m2
0 (0%) [4 (40%])
--
nd
Fair
Up to 8 y (nd)
Alternate-day prednisone
Lactose
8 (8)
10 (10)
99 mg/h/m2
1 (13%) [2 (20%)]
RR 0.63 (0.07-5.72)
94
0.677
Fair
nd
Poor
33 (33)
RR 0.93 (0.37-2.33)
97
RR 0.70 (0.38-1.28)
98
Calculated by ERT Calculated by ERT 95 Calculated by ERT 96 Calculated by ERT 97 Calculated by ERT 98 Calculated by ERT
93 94
63 mo (41 mo)
Alternate-day prednisone
Placebo
44 (47)
33 (33)
RR 1.13 (0.20-6.35)
99
0.894 nd
Fair Fair
--
99
Calculated by ERT
Supplementary table 37. Summary table of RCTs examining alternate-day prednisone treatment vs. control in patients with MPGN (continuous outcomes)
Outcome Proteinuria Proteinuria SCr/GFR/CrCl SCr MotaHernandez 1985[58] Mexico 6.5 y (nd) Alternate-day prednisone Lactose 8 (8) 10 (10) SCr 0.78 mg/dl 99 mg/h/m2 mg/dl 0.78 (0.82) -0.50 (+4.09) nd Poor MotaHernandez 1985[58] Mexico 6.5 y (nd) Alternate-day prednisone Lactose 8 (8) 10 (10) SCr 0.78 mg/dl 99 mg/h/m2 mg/h/m2 99 (97) -3.63 (-0.05) nd Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 38. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (categorical outcomes)
Outcome ESRD ESRD (dialysis) Donadio 100 1984[19] US 7 y (12 mo) Dipyridamole and aspirin Placebo 21 (25) 19 (25) GFR 69.5 ml/min/1.73 m2 5.9 g/d Mean 62 (range 37-70) mo [33 (10-63)] -3 (14%) [9 (47%)] RR 0.030 (0.10-0.95)
101
0.03102
Fair
Kidney Function Donadio 103 GFR by 1984[19] 25% US No. of nephrotic Zauner patients 1994[92] No. of Germany nephrotic patients Adverse Events AE- painful ecchymosis AErecurrent gastric ulcer with Donadio 105 bleeding 1984[19] AE-rectal US bleeding AE-acute interstitial nephritis due to furosemide
Dipyridamole and aspirin Dipyridamole aspirin, protein restriction and antiHTN therapy
21 (25)
19 (25)
5.9 g/d
RR 0.39 (0.12-1.29)
104
<0.05 nd nd
---
10 (10)
8 (8)
8.28 g/d
--
nd
Fair
--
nd
Fair
12 mo (12 mo)
Placebo
21 (25)
19 (25)
5.9 g/d
--
5% [0%] 0% [5%]
--
nd
Fair
--
nd
Fair
Subsequent publication (Donadio JV. 1989 AJKD Dec 14(5): 445) indicated that results are heavily influenced by lead-time bias, so no evidence profile was made. Calculated by ERT 102 Calculated by ERT. Odds ratio 103 Subsequent publication (Donadio JV. 1989 AJKD Dec 14(5): 445) indicated that results are heavily influenced by lead-time bias, so no evidence profile was made. 104 Calculated by ERT 105 Subsequent publication (Donadio JV. 1989 AJKD Dec 14(5): 445) indicated that results are heavily influenced by lead-time bias, so no evidence profile was made.
100 101
Supplementary table 39. Summary table of studies examining dipyridamole plus aspirin treatment vs. placebo in patients with MPGN (continuous outcomes)
Outcome Proteinuria 12 mo 36 mo SCr/GFR/CrCl GFR 12 mo SCr 12 mo Donadio 106 1984[19] US Zauner 1994[92] Germany 12 mo (12 mo) Dipyridamol e and aspirin Dipyridamol e aspirin, protein restriction and antiHTN therapy Placebo Protein restricti on and antiHTN therapy 18107 (25) 18 (25) GFR 69.5 ml/min/1.73 m2 5.9 g/d ml/min/1. 73 m2 mg/dl NA NA -1.3 (-19.6) +0.18 (+1.1) -0.01 (-0.18) 0.05 <0.02108 NS Poor Poor Zauner 1994[92] Germany 12 mo (36 mo) Dipyridamol e aspirin, protein restriction and antiHTN therapy Protein restricti on and antiHTN therapy g/d 10 (10) 8 (8) SCr 1.79 mg/dl 8.28 g/d g/d 8.28 (7.11) 8.28 (7.11) -5.72 (-1.7) -6.67 (-2.77) nd nd Poor Poor Study, Year Country Duration Outcome measuremen t (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
SCr
36 mo (36 mo)
10 (10)
8 (8)
8.28 g/d
mg/dl
1.79 (1.79)
nd
Poor
Subsequent publication (Donadio JV. 1989 AJKD Dec 14(5): 445) indicated that results are heavily influenced by lead-time bias, so no evidence profile was made. Restricted to those without treatment complications. 108 By 2-sample t-test and by rank-sum test, respectively.
106 107
Supplementary table 40. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (categorical outcomes)
Outcome ESRD ESRD Kidney function SCr >0.2 mg/dl SCr >0.2 mg/dl Significant 1/ SCr (P<0.05) Doubling of SCr Zimmerman 1983[93] US 12 mo (12 mo) Warfarin and dipyridamole No treatment 8 (11) 10 (11) SCr 1.6 mg/dl 2.91 g/d 1 (13%) [6 (60%)] 2 (25%) [0 (0%)] 0 (0%) [5 (50%)] 0 (0%) [4 (40%)] RR 0.21 (0.03-1.40) ---0.06 (X2) nd <0.03 nd Poor Poor Poor Poor Zimmerman 1983[93] US 12 mo (12 mo) Warfarin and dipyridamole No treatment 8 (11) 10 (11) SCr 1.6 mg/dl 2.91 g/d 0 (0%) [2 (20%)] -nd Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention OR/RR/HR [Control] P value Quality
Supplementary table 41. Summary table of study examining warfarin plus dipyridamole treatment vs. control in patients with MPGN (continuous outcomes)
Outcome Proteinuria Urine protein SCr/GFR/CrCl SCr 1/SCr slope Zimmerman 1983[93] US 12 mo (12 mo) Warfarin and dipyridamole No treatment 8 (11) 10 (11) mg/dl SCr 1.6 mg/dl 2.91 g/d dl/mg 1.6 (1.6) --0.2 (+2.0) +0.091 (-0.208) <0.01 <0.025 Poor Poor Zimmerman 1983[93] US 12 mo (12 mo) Warfarin and dipyridamole No treatment 8 (11) 10 (11) SCr 1.6 mg/dl 2.91 g/d g/d 6.2 (6.8) -3.0 (-0.1) NS (<0.10) Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 42. Summary table of studies examining prednisone or CsA treatment vs. control in patients with schistosoma and nephropathy (categorical outcomes)
Outcome Remission Complete remission Sobh 1989[74] Netherlands Partial remission Kidney Function Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel Oxamniquine +praziquantel Oxamniquine +praziquantel Oxamniquine +praziquantel Oxamniquine +praziquantel Oxamniquine +praziquantel 10 (10) 8 (8) 10 (10) 8 (8) 10 (10) 8 (8) SCr 0.99 SCr 0.68 8 (8) SCr 0.99 SCr 0.68 4.47 g/d 2.92 g/d 4.47 g/d 2.92 g/d 0 (0%) [1 (13%)] 1 (13%) [1 (13%)] 2 (20%) [0 (0%)] 0 (0%) [0 (0%)] 2 (20%) [0 (0%)] 2 (25%) [0 (0%)] -RR 1.00 (0.07-13.37)
111
Description Intervention Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Control
Results Events (%) Intervention RR/OR/HR [Control] 2 (20%) [0 (0%)] 1 (13%) [0 (0%)] 3 (30%) [1 (13%)] 1 (13%) [1 (13%)] --RR 2.40 (0.3018.90)109 RR 1.00 (0.07-13.37)
110
P value
Quality
nd nd nd nd
12 mo (3 d)
nd nd nd nd
---
Adverse Events Drug toxicity Sobh 1989[74] Netherlands SCr 0.99 8 (8) SCr 0.68 2.92 g/d 4.47 g/d --nd nd Poor Poor 12 mo (3 d)
Supplementary table 43. Summary table of studies examining prednisone or cyclosporine treatment vs. control in patients with schistosoma and nephropathy (continuous outcomes)
Outcome Proteinuria 24-h proteinuria SCr/GFR/CrCl Sobh 1989[74] Netherlands 12 mo (3 d) Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel Oxamniquine +praziquantel 10 (10) 8 (8) SCr 0.99 8 (8) SCr 0.68 2.92 g/d 4.47 g/d nd nd 0.68 (0.82) -0.14 (+0.03) nd Poor 0.99 (0.82) -0.04 (+0.03) nd Poor Sobh 1989[74] Netherlands 12 mo (3 d) Oxamniquine +praziquantel + prednisone Oxamniquine +praziquantel +CsA Oxamniquine +praziquantel Oxamniquine +praziquantel 10 (10) 8 (8) SCr 0.99 8 (8) SCr 0.68 2.92 g/d 4.47 g/d nd g/d 2.92 (3.9) +0.64 (+0.03) nd Poor 4.47 (3.9) -0.55 (+0.09) nd Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
SCr
Supplementary table 44. Evidence profile of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy
Outcome Mortality ESRD Complete remission Partial remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 1 RCT (High) 0 RCTs 0 RCTs 0 RCTs 2 RCTs (High) 3 RCTs (High) 4 RCTs (High) 6 RCTs (High) 2 RCTs Total N (treatment) -109 (55) ---104 (52) 148 (75) 227 (116) 424 (213) 149 (77) Methodological quality of studies per outcome -Some limitations (-1) ---No limitations (0) Some limitations (-1) Some limitations (-1) Some limitations (-1) Consistency across studies -N/A ---Important inconsistencies (-1) No important inconsistencies (0) No important inconsistencies (0) No important inconsistencies (0) Directness of the evidence generalizability/ applicability -Direct (0) ---Direct (0) Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for Qualitative and quantitative description outcome of effect -Sparse (-1) Imprecision (-1) ---None (0) None (0) None (0) None (0) -Very low ---Moderate Moderate Moderate Moderate -Insufficient evidence ---Benefit for ACE-I or ARB without steroids. No difference with steroids Benefit for ACE-I or ARB Benefit for ACE-I or ARB Benefit for ACE-I or ARB No difference in major adverse event Importance of outcome Critical Critical High High High High High Moderate Moderate Moderate
Supplementary table 45. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD Time to doubling of baseline SCr or ESRD Proteinuria Proteinuria <500 mg/d/1.73 m2 lasting 6 mo (All) Proteinuria <500 mg/d/1.73 m2 lasting 6 mo (children only) Proteinuria <160 mg/d/1.73 m2 lasting 6 mo (All) Proteinuria <160 mg/d/1.73 m2 lasting 6 mo (children only) Urine protein 50% Study, Year Country Duration Outcome measurement (Treatment) 2y (2 y) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR Proteinuria Results Events (%) RR/OR/HR Intervention (95% CI) [Control] 1 (1%) [4 (7%)] Estimated OR 0.23 (0.03-2.21) P value Quality
Valsartan, 80 mg/d
Placebo
54 (54)
55 (55)
1.8 g/d
Fair
41% [9%]
nd
0.0002
50% [11%] Coppo 2007[17] Europe 38 mo (38 mo) Benazepril 0.2 mg/kg/d Placebo 32 (32) 34 (34) eGFR 116 ml/min/1.73m2 1.6 g/d 13% [0 (0%)]
nd
nd Good
--
0.02
--
nd
24 mo (24 mo)
Prednisone taper
20 (20)
18 (18)
1.6 g/d
Fair
Kidney Function CrCl 30% CrCl 30% or proteinuria >3.5 g/d/1.73 m2 SCr 50% Coppo 2007[17] Europe Praga 38 mo (38 mo) 76 mo Benazepril 0.2 mg/kg/d ACE-I Placebo 32 (32) 23 34 (34) 21 eGFR 116 ml/min/1.73m2 GFR 102 1.6 g/d Fair Good Good
No ACE-I
2 g/d
112 113
Outcome
No. Analyzed (Enrolled) Intervention (23) Control (21) GFR ml/min SCr 1.0 mg/dl Proteinuria (>3.5 g/d: 11%)
76 mo (76 mo) 24 mo (24 mo) Losartan 50 mg/d, prednisone taper Valsartan, 80 mg/d Losartan 50 mg/d, prednisone taper Prednisone taper 20 (20) 18 (18) GFR 104 ml/min/1.73m2 SCr 0.8 mg/dl GFR 87 ml/min SCr 1.11 mg/dl GFR 104 ml/min/1.73m2 SCr 0.8 mg/dl 1.6 g/d
Results Events (%) RR/OR/HR Intervention (95% CI) [Control] (0.07[12 (57%)] 0.70)115 0 (0%) -[~6 (30%)] RR 0.20 ~2 (8%) (0.05[~9 (45%)] 0.83)116 RR 0.25 3 (13%)117 (0.08[11 (52%)] 0.77)118 nd (0%?) [4 (22%)] RD -0.22119
P value
Quality
nd
Poor
Adverse Event Major Li 2006[50] adverse Hong Kong event AE: Postural hypotension Horita 2007[36] Japan
2y (2 y) 24 mo (24 mo)
54 (54) 22 (22)
55 (55) 18 (18)
1.8 g/d
NS (0.664) nd
Good
1.6 g/d
Fair
114 SCr at baseline in the three enalapril-treated patients who reached the primary end point were 0.9, 1.4, and 1.4 mg/dl, corresponding to creatinine clearances of 120, 75, and 60 ml/min, respectively. 115 Calculated by ERT 116 Calculated by ERT 117 Same 3 participants as for SCr 50% increase. 118 Calculated by ERT 119 Calculated (P=0.02) 120 Calculated by ERT 121 Calculated (NS)
Supplementary table 46. Summary table of RCTs examining ACE-I or ARB in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria 12 wk (2 y) 24 wk (2 y) 52 wk (2 y) 76 wk (2 y) 104 wk (2 y) 2y (2 y) Praga 2003[68] Spain Shimizu 2008[73] Japan Horita 2007[36] Japan 76 mo (76 mo) 1y 6 mo 24 mo (24 mo) ACE-I 5-40 mg/d BP<140/90 Losartan Losartan 50 mg/d, prednisone taper GFR 102 ml/min SCr 1.0 mg/dl GFR 72 ml/min SCr 1.0 mg/dl GFR 104 ml/min/1.73m2 SCr 0.8 mg/dl 2 g/d (>3.5 g/d: 11%) 0.81 g/d 1.80 (2.35) 1.80 (2.35) 1.80 (2.35) 1.80 (2.35) 1.80 (2.35) 1.80 (2.35) 1.80 (2.35) 2.0 (1.7) 0.81 (0.73) 1.6 (1.6) 0.35 (0.19) 1.0 (0) 0.54 (0.38) 0.46 (0.24) 0.57 (0.38) -0.66 (+0.08) -33.5 (+15.0) -1.1 (+0.3) -0.8 (-36%) [+0.1 (+23%)] -0.36 (-0.10) -1.3 (-1.1) 0.005 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Good <0.001 NS Poor Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Valsartan, 80 mg/d
Placebo
54 (54)
55 (55)
1.8 g/d
g/d
Proteinuria
g/d
Proteinuria
g/d
Proteinuria SCr/GFR/CrCl Mean rates of GFR throughout study period Mean rates of GFR 12 to 104 wks CrCl SCr CrCl CrCl
1.6 g/d
g/24h
<0.05
Fair
2y (2 y)
Valsartan, 80 mg/d
Placebo
54 (54)
55 (55)
GFR 102 ml/min SCr 1.0 mg/dl eGFR 116 ml/min/1.73m2 GFR 104 ml/min/1.73m2
Outcome
Study, Year Country Japan Shi 2002[72] China Shimizu 2008[73] Japan
No. Analyzed (Enrolled) GFR/SCr Intervention Control SCr 0.8 mg/dl Proteinuria Units mg/dl ml/min
Results Baseline Intervention (Control) 0.8 (0.7) 78.55 (78.20) 125.07 (106.55) 72.0 (75.4) 1.0 (0.9) Intervention (Control) 0 (+0.2) -9.4 (-7.9) Follow-up: -8.01 (+47.85) -0.2 (+0.7) -0.1 (0) P value Quality
18 mo
ACE-I
44 (65)
39 (66)
NS
Poor
12 mo (12 mo)
Losartan
Antiplatelet agents
18 (18)
18 (18)
NS Poor NS
Supplementary table 47. Evidence profile of RCTs examining steroid regimens in biopsy-proven IgA nephropathy
Outcome Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 4 RCTs (High) 0 RCTs 0 RCTs 3 RCTs (High) 3 RCTs (High) 6 RCTs (High) 5 RCTs (High) 1 RCT Total N (treatment) -336 (164) --250 (121) 179 (90) 367 (180) 363 (179) 60 (29) Methodological quality of studies per outcome -Some limitations (-1) --Some limitations (-1) Serious limitations (-2) Some limitations (-1) Some limitations (-1) Consistency across studies -No important inconsistencies (0) --No important inconsistencies (0) No important inconsistencies (0) No important inconsistencies (0) No important inconsistencies (0) Directness of the evidence generalizability/ applicability* -Some uncertainty (-1) --Some uncertainty (-1) Some uncertainty (-1) Some uncertainty (-1) Some uncertainty (-1) Other considerations Quality of evidence for outcome -None (0) --None (0) None (0) None (0) None (0) -Low --Low Summary of findings Qualitative and quantitative description of effect -Benefit for steroids. No difference between low dose steroid and no steroid in one trial --Benefit for steroid122 Importance of outcome Critical Critical High High High
Very low
High
Low Low
* Generalizability was evaluated with regard to optimized therapy of proteinuria and hypertension with angiotensin converting enzyme (ACE-I) or angiotensin receptor blockage (ARB)
122 123
Among patients with a mean proteinuria of 2 g/d. Among patients with a mean proteinuria of 2 g/d or more.
Supplementary table 48. Meta-analyses and systematic reviews on immunosuppression for IgA nephropathy
Study, Year Samuels 2004[70] Database: Medline, Embase, Cochrane renal registry, ASN conference Proceedings, Experts Search Dates: Until 2002 N Studies: 13 trials (16 publications) N Subjects: 623 Study Eligibility Criteria Head-to-head or placebo/no treatment randomized trials evaluating the effects of different immunosuppressive agents with biopsy proven IgA nephropathy. Both Adults and pediatric patients Interventions (Studies) Efficacy of steroids (7 trials) Efficacy of Immunosuppressive agents + steroids (3 trials) Efficacy of Immunosuppressive agents alone (3 trials) Outcomes Risk of ESRD (need for dialysis) Doubling of serum creatinine Glomerular filtration rate (GFR or CrCl) Urinary Protein Excretion (g/24hr) Conclusions Use of steroids in IgA nephropathy significantly reduced risk of ESRD, the doubling of serum creatinine, and a significant reduction in urinary protein excretion. Similar efficacy was not noted for kidney function with use of Immunosuppressive agents + steroids or Immunosuppressive agents alone Immunosuppressive agents alone were associated with reduction in urinary protein excretion. Comments Is Eligibility criteria similar to the guideline Yes/No Yes (biopsy proven IgA nephropathy; clinical trials)
No
Yes
Lack of details on adverse events in published studies Significant heterogeneity as a potential source for reduction in urinary protein excretion with Immunosuppressive agents, which had no significant treatment effect on kidney function parameters. Less applicable to early stages of IgA nephropathy Suboptimal quality of trial reporting Insufficient data to explore whether the duration of treatment or disease severity influenced the effect of treatment N studies (N intervention group/ total N) 6 (160/341) 6 (160/341) 4 (67/138) 5 (127/263) Test for heterogeneity P-value I2 Statistic 0% 0% 53.2% 0% Pvalue NS NS 0.09 NS
Intervention
Control
Outcome
Mean follow up
Baseline kidney function/proteinuria 2 studies: CrCl >25 ml/min/1.73m2 or >70 ml/min 2 studies: SCr >136mol/L 1 study: SCr <132 mol/L 1 study: UPE <1.5g/d 1 study: no data
Pooled RR1(95% CI) 0.44 (0.25, 0.80) 0.45 (0.29, 0.69) WMD 17.87 (4.93, 30.82) WMD 0.49 (0.72, 0.25)
Urinary protein Steroid excretion (g/24h) Comments The systematic review did not report ACE-I use in the control arm or as co-medications * Except for Shoji AJKD 2000, all studies had 6-130 mo follow-up. Shoji 2000 had 3 mo follow-up. ^ Except for Lai BMJ 1987, all studies had 23 mo and 36 mo follow-up. Lai 1987 had 3 mo follow-up. Errors noted in text (page 179) and figure 6, 7.
Supplementary table 49. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD Doubling of SCr or ESRD ESRD Manno 2009[53] Italy Prednisone, ramipril Target BP <120 80 mmHg 24-h proteinuria to 1.0 g Ramipril Target BP <12080 mmHg 24-h proteinuria to 1.0 g 4 wk wash-out 100% 2 (4%) [13 (27%)] 1 (2%) [7 (14%)] 28 (97%) [23 (76%)] 28 (97%) [19 (66%)] 97% [53%] Prednisone, antiHTN, and antiplatelet agents as needed Anti-HTN, and antiplatelet agents as needed 43 (43) 43 (43) GFR 93 ml/min SCr 972 mol/L 2.0 g/d 14% 1 (2%) [5 (12%)] 95% [74%] 43 (43) 47 (47) GFR 901 ml/min/1.73 m2 252 mg/dl 2% 3 (7%) [3 (6%)] RR 1.09 (0.235.13)129 RR 0.16 (0.040.66)124 RR 0.15 (0.021.14)125 RR 1.30 (1.051.62)126 RR 1.58 (1.182.10)127 RR 0.06 (0.01-0.44) RR 0.20 (0.021.64)128 0.011 NS (0.067) 0.018 Fair 0.002 0.0003 nd Good Fair Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use Results Events (%) Intervention RR/OR/HR [Control] P value Quality
8y (6 mo)
48 (48)
49 (49)
1.7 g/d
Good
Kidney survival
Lv 2009[51] China
29 (30)
31 (33)
2.0 g/d
4 wk wash-out 100%
Pozzi 2004[66] Italy Pozzi 1999[65] Italy (Multicenter) Katafuchi 2003[46] Japan
Kidney survival
5y (6 mo) 5y (2 y)
0.04
Fair
ESRD Proteinuria
Low dose steroid, dipyridamole Prednisone, ramipril Target BP <120 80 mmHg 24-h proteinuria to 1.0 g
NS
Fair
Proteinuria <1g
8y (6 mo)
48 (48)
49 (49)
1.7 g/24h
4 wk wash-out 100%
RR 1.11 (0.861.44)130
NS (0.407)
Good
Calculated by ERT Calculated by ERT 126 Calculated by ERT 127 Calculated by ERT 128 Calculated by ERT 129 Calculated by ERT 130 Calculated by ERT
124 125
Outcome
Duration Outcome measurement (Treatment) 6 mo (nd) 1y (nd) 6 mo (6 mo) 1y (6 mo) 6 mo (6 mo) 1y (6 mo) 3y (2 y) 5y (6 mo) 7y (6 mo) 3y (4 mo) 7 mo (nd)
No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use 4 wk wash-out 100%
Proteinuria >50% Minimal response <1g/d proteinuria Optimal response <0.5g/d proteinuria Kidney Function Kidney function, CrCl <60% baseline Progression of renal disease (SCr 50%) Doubling of SCr (SCr 100%)) CKD (CrCl>15%) Adverse Events Major adverse events
Lv 2009[51] China
Cilazapril+steroid
Cilazapril
29 (30)
31 (33)
2.0 g/d
Steroids
Supportive therapy
43 (43)
43 (43)
2.0 g/d
14%
Results Events (%) Intervention RR/OR/HR [Control] RR 2.35 22 (71%) (1.36[10 (34%)] 4.08)131 81% (58%) RR 2.11 44% [21%] (1.08-4.13) RR 2.38 72% [30%] (1.46-3.90) RR 4.00 19% [5%] (0.90-17.76) 11 (26%) RR 5.50 [2 (5%)] (1.30-23) 2 (9.2%132) [4 (8.7%)] 9 (21%) [14 (33%)] HR133 0.31 (0.05, 1.8) RR 0.41 (0.17-0.98) RR 0.08 (0.010.56)134 RR 0.67 (0.133.50)135 --
P value nd
Quality
Hogg 2006[35] US, Canada Pozzi 1999[65] Italy (Multicenter) Pozzi 2004[66] Italy Lai 1986[48] Hong Kong Lv 2009[51] China
Prednisone taper (8040 mg every other day Prednisone, antiHTN, and antiplatelet agents as needed
Placebo
30 (30)
29 (29)
UPCR 2.2
53% [48%]
NS
Good
0.04 Fair
43 (43)
43 (43)
2.0 g/d
Prednisone
No prednisone
17 (17) 29 (30)
17 (17) 31 (33)
6.5 g/d
nd 4 wk wash-out 100%
Poor
Cilazapril+steroid
Cilazapril
2.0 g/d
nd
Fair
Calculated by ERT Estimated cumulative proportion of failures at 3 years 133 Controlled for baseline UPCR. Both also NS without adjusting for baseline UP/C 134 Calculated by ERT 135 Calculated by ERT
131 132
Supplementary table 50. Summary table of RCTs examining steroid regimens in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria Time averaged proteinuria UPCR Study, Year Country Duration Outcome measurement (Treatment) 1y (nd) 3y (2 y) 5y (2 y) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use 4 wk wash-out 100% 53% [48%] Units Results Baseline Intervention (Control) 2.5 (2.0) 2.2 (1.4) 252 (143) Intervention (Control) -1.5 (-0.4) P value Quality
Lv 2009[51] China Hogg 2006[35] US, Canada Katafuchi 2003[46] Japan Pozzi 1999[65] Italy (Multicenter) Lai 1986[48] Hong Kong Julian, 1993[44] US
Cilazapril+st eroid Prednisone taper (8040 mg every other day Low dose steroid, dipyridamole Prednisone, anti-HTN, and antiplatelet agents as needed Prednisone Alternate day prednisone Prednisone, ramipril Target BP <12080 mmHg 24-h proteinuria to 1.0 g Low dose steroid, dipyridamole Prednisone taper (8040 mg every other day
Cilazapril
SCr 1.1 mg/dl GFR 102 ml/min/1.73 m2 GFR 109 ml/min/1.73 m2 GFR 91 ml/min/1.73 m2
2.0 g/d
g/d
0.01
Good
Placebo
UPCR 2.2
None
nd
<0.05
Poor
Urinary protein
Dipyridamol e Anti-HTN, and antiplatelet agents as needed No prednisone No prednisone Ramipril Target BP <12080 mmHg 24-h proteinuria to 1.0 g Dipyridamol e
252 mg/dl
2%
mg/dl
-134 (-43)
nd
Fair
Proteinuria (median)
5y (6 mo) 3y (4 mo) 1y (1 y)
43 (43) 17 (17)
2.0 g/d
14%
g/d
<0.05
Fair
Proteinuria Proteinuria
6.5 g/d nd
nd 40%
g/d nd
nd nd
Poor Fair
Kidney Function
8y (6 mo)
48 (48)
49 (49)
1.7 g/24h
4 wk wash-out 100%
ml/min/ 1.73m2 /y
100.4 (97.5)
0.56 (6.17)
0.013
Good
SCr
5y (2 y) 3y (2 y)
43 (43) 30 (30)
47 (47) 29 (29)
252 mg/dl
2%
mg/dl
NS
Fair
SCr
Placebo
UPCR 2.2
53% [48%]
mg/dl
nd
Poor
Outcome
Description Intervention Alternateday prednisolone 510 mg dipyridamole or zilazep 150 or 300 mg/d Prednisone Alternate day prednisone Control
No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use Units
Intervention (Control)
P value
Quality
SCr
2y (2 y)
24 (24)
24 (24)
0.97 g/d
23%
mg/dl
0.92 (1.15)
0 (+0.03)
NS
Poor
3y (4 mo) 1y (1 y)
No prednisone No prednisone
17 (17) 35 (35)
17 (17)
ml/min GFR 68 ml/min 6.5 g/d nd mol/l SCr 135 mol/l 3.5 g/d 40% mol/l
nd NS (0.06)
Poor
Fair
Supplementary table 51. Meta-analyses and systematic reviews on immunosuppression for IgA nephropathy
Study, Year Samuels 2004[70] Database: Medline, Embase, Cochrane renal registry, ASN conference Proceedings, Experts Search Dates: Until 2002 N Studies: 13 trials (16 publications) N Subjects: 623 Study Eligibility Criteria Head-to-head or placebo/no treatment randomized trials evaluating the effects of different immunosuppressive agents with biopsy proven IgA nephropathy. Both Adults and pediatric patients Interventions (Studies) Efficacy of steroids (7 trials) Efficacy of Immunosuppressive agents + steroids (3 trials) Efficacy of Immunosuppressive agents alone (3 trials) Outcomes Risk of ESRD (need for dialysis) Doubling of serum creatinine Glomerular filtration rate (GFR or CrCl) Urinary Protein Excretion (g/24hr) Conclusions Use of steroids in IgA nephropathy significantly reduced risk of ESRD, the doubling of serum creatinine, and a significant reduction in urinary protein excretion. Similar efficacy was not noted for kidney function with use of Immunosuppressive agents + steroids or Immunosuppressive agents alone Immunosuppressive agents alone were associated with reduction in urinary protein excretion. Comments Is Eligibility criteria similar to the guideline Yes/No Yes (biopsy proven IgA nephropathy; clinical trials)
No
Yes
Lack of details on adverse events in published studies Significant heterogeneity as a potential source for reduction in urinary protein excretion with Immunosuppressive agents, which had no significant treatment effect on kidney function parameters. Less applicable to early stages of IgA nephropathy Suboptimal quality of trial reporting Insufficient data to explore whether the duration of treatment or disease severity influenced the effect of treatment N studies (N intervention group/ total N) 2 (total 106) 3 (63 / 122) 2 (total 152) 3 (79 / 153) Test for heterogeneity I2 Statistic 0% P-value NS
Intervention Immunosuppressive agents or cyclosporine alone Immunosuppressive agents or cyclosporine alone Immunosuppressive agents + steroids Immunosuppressive agents + steroids
Control
Outcome
Mean follow up
Baseline kidney function/proteinuria 1 study: SCr >130mol/l 1 study: well preserved kidney function 1 study: No clinical inclusion criteria 2 studies: No clinical inclusion criteria 1 study: Proteinuria >1.5 g/d or CrCl >5 ml/min/1.73m2
Pooled RR1(95% CI) 0.35 (0.04, 3.22) WMD 0.94 (1.43, -0.46) 0.59 (0.06, 6.03) WMD -1.25 (2.71, 0.21)
Pvalue
NS
0.0001 NS 0.09
48.7% nd 97.3%
NS nd <0.0001
Urinary 23, 36 mo* protein excretion (g/24hr) Comments The systematic review did not report ACE-I use in the control arm or as co-medications * Except for Shoji AJKD 2000, all studies had 6-130 mo follow-up. Shoji 2000 had 3 mo follow-up. ^ Except for Lai BMJ 1987, all studies had 23 mo and 36 mo follow-up. Lai 1987 had 3 mo follow-up. Errors noted in text (page 179) and figure 6, 7.
Supplementary table 52. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD Renal survival Ballardie 2002[6] UK 5y (2 y) 5y (4 mo) Prednisolone, cyclophosphamide BP <160/90 mmHg Prednisolone, AZA DBP<90 mmHg BP <160/90 mmHg DBP<90 mmHg 19 (19) 21 (21) 19 (19) 22 (22) SCr >130mol/l SCr 0.8 mg/dl 3.9 g/24h 26% 72% [5%] 0 (0%) [3 (14%)] Treatment discontinuation due to mild leukopenia or transaminase n=3 [treatment discontinuation due to bleeding n=2] 0.04 Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria ACE-I or ARB use Results Events (%) Intervention [Control] RR/OR /HR P value Quali ty
Proteinuria Patients with Harmankaya proteinuria 2002[32] >500 mg/d Turkey Adverse events
nd
0%
--
nd
Poor
2y (2 y)
40 (40)
34 (34)
1.35 g/d
0%
--
--
Fair
Supplementary table 53. Summary table of RCTs examining steroid and immunosuppressive regimens in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria Proteinuria Ballardie 2002[6] UK Yoshikawa 1999[89] Japan (Multicenter) 5y (2 y) 2y (2 y) Prednisolone, cyclophosphamide BP <160/90 mmHg Prednisolone, AZA, heparin, warfarin, and dipyridamole Prednisolone, cyclophosphamide BP <160/90 mmHg Prednisolone, AZA DBP<90 mmHg Prednisolone, AZA, heparin, warfarin, and dipyridamole BP <160/90 mmHg Heparin, warfarin, and dipyridamole BP <160/90 mmHg DBP<90 mmHg Heparin, warfarin, and dipyridamole 19 (19) 40 (40) 19 (19) 34 (34) SCr >130 mol/l SCr 0.64 mg/dl 3.9 g/24h 26% g/24h 3.9 (4.6) 1.35 (0.98) -3.6 (-0.63) -1.13 (-0.10) nd Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria ACE-I or ARB use Results Units Baseline Intervention (Control) Intervention (Control) P value Quality
UPE
1.35 g/d
0%
g/d
nd
Fair
SCr/GFR/CrCl Rate Ballardie kidney 2002[6] UK function Harmankaya SCr 2002[32] Turkey Yoshikawa 1999[89] CrCl Japan (Multicenter)
5y (2 y) 5y (4 mo) 2y (2 y)
3.9 g/24h nd
26% 0%
nd NS
Poor Poor
1.35 g/d
0%
NS
Fair
Supplementary table 54. Evidence profile of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy
Outcome # of studies and study design 1 RCT (High) 1 RCT (High) 0 RCTs 0 RCTs 2 RCTs (High) 2 RCTs (High) 2 RCTs (High) 1 RCT (High) 1 RCT Total N (treatment) 207 (101) 207 (101) --287 (141) 287 (141) 287 (141) 80 (40) 207 (101) Methodological quality of studies per outcome No limitations (0) No limitations (0) --No limitations (0) No limitations (0) No limitations (0) No limitations (0) Consistency across studies N/A N/A --Important inconsistencies (-1) Important inconsistencies (-1) No inconsistencies (0) N/A Directness of the evidence generalizability/ applicability Direct (0) Direct (0) --Direct (0) Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome Sparse (-1) Sparse (-1) --None (0) None (0) None (0) Sparse (-1) Low Low --Moderate Moderate High Moderate Qualitative and quantitative description of effect No difference No difference --Possible harm No difference No difference No difference Treatment-related major side effects for AZA Importance of outcome Critical Critical High High High High Moderate Moderate Moderate
Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
Balance of potential benefits and harm: Possible worsening, more side effects with AZA
Supplementary table 55. Summary table of RCTs examining AZA in combination vs. AZA along in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome Proteinuria Proteinuria disappearance (<0.1 g/m2/d) Proteinuria >50% from baseline SCr/GFR/CrCl CrCl <60 ml/min/1.73m2 SCr >50% from baseline Study, Year Country Yoshikawa 2006[90] Japan Pozzi 2010[67] Italy and Switzerland Yoshikawa 2006[90] Japan Pozzi 2010[67] Italy and Switzerland Duration Outcome measurement (Treatment) 24 mo (24 mo) 5y (6 mo) 24 mo (24 mo) 5y (6 mo) Description Intervention AZA, warfarin, dipyridamole, prednisolone AZA, prednisone alternate day AZA, warfarin, dipyridamole, prednisolone AZA, prednisone alternate day Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use Results Events (%) Intervention RR/OR/HR [Control] 36 (92%) [29 (74%)] 45 (45%) [53 (50%)] 0% [0%] 13 (13%) [12 (11%)] RR 1.24 (1.011.52)136 RR 0.89 (0.671.19)137 -RR 1.14138 (0.54-2.37) P value Quality
GFR 147 ml/min/1.73 m2 Scr 49 mol/l GFR 66 ml/min/1.73 m2 Scr 106 mol/l GFR 147 ml/min/1.73 m2 Scr 49 mol/l GFR 66 ml/min/1.73 m2 Scr 106 mol/l
0% 46%
0.039 NS
Good Good
0% 46%
NS NS
Good Good
136 137
Supplementary table 56. Summary table of RCTs examining AZA in combination vs. AZA alone in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria UPE Yoshikawa 2006[90] Japan Pozzi 2010[67] Italy and Switzerland 2y (2 y) AZA, warfarin, dipyridamole, prednisolone AZA, prednisone alternate day Prednisolone 39 (40) 39 (40) GFR 147 ml/min/1.73 m2 Scr 49 mol/l GFR 66 ml/min/1.73 m2 Scr 106 mol/l GFR 147 ml/min/1.73 m2 Scr 49 mol/l 1.30 g/m2/d 0% g/m2/d 1.29 (1.16) -1.19 (-1.04) NS Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
UPE
5y (6 mo)
101 (101)
106 (106)
2.0 g/d
46%
g/d
2.10 (1.95)
-0.94 (-0.97)
NS
Good
SCr/GFR/CrCl CrCl Biopsy Glomeruli showing sclerosis Glomeruli showing crescents Glomeruli showing capsular adhesion s Yoshikawa 2006[90] Japan 24 mo (24 mo) AZA, warfarin, dipyridamole, prednisolone Prednisolone 39 (40) 39 (40) 1.30 g/m2/d 0% ml/min/ 1.73 m
2
148 (156)
+8 (-1)
NS
Good
5.0 (3.1) Yoshikawa 2006[90] Japan 24 mo (24 mo) AZA, warfarin, dipyridamole, prednisolone 32 (40) 30 (40) GFR 147 ml/min/1.73 m2 Scr 49 mol/l 17.3 (19.1) 5.2 (3.6)
nd nd Good nd
Prednisolone
1.30
g/m2/d
0%
Supplementary table 57. Evidence profile of RCTs examining MMF in biopsy-proven IgA nephropathy
Outcome Mortality ESRD Complete remission Partial remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events # of studies and study design 0 RCTs 3 RCTs (High) 0 RCTs 0 RCTs 0 RCTs 2 RCTs (High) 2 RCTs (High) 2 RCTs (High) 2 RCTs (High) 3 RCTs Total N (treatment) -106 (58) ---72 (37) 66 (38) 74 (41) 74 (41) 106 (58) Methodological quality of studies per outcome -Some limitations (-1) ---Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Consistency across studies -Important inconsistencies (-1) ---No inconsistencies Important inconsistencies (-1) No inconsistencies Important inconsistencies (-1) Directness of the evidence generalizability/ applicability -Direct (0) ---Direct (0) Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome -None (0) ---Sparse (-1) Sparse (-1) Sparse (-1) Sparse (-1) -Low ---Low Very Low Low Very Low Qualitative and quantitative description of effect -No difference for MMF vs. placebo ---No difference for MMF vs. placebo No difference for MMF vs. placebo No difference for MMF vs. placebo No difference for MMF vs. placebo Dose reduction due to side effects for MMF Importance of outcome Critical Critical High High High High High Moderate Moderate Moderate
Supplementary table 58. Meta-analyses and systematic reviews on MMF therapy for IgA nephropathy
Study, Year Xu 2008[86] Database: PubMed, Cochrane (No language restriction) Search Dates: Until April 2008 N Studies: 4 N Subjects: 168 Study Eligibility Criteria Included: only reports of RCTs that were conducted on adult humans and which used MMF as the intervention. Excluded: Those that did not clearly report the numbers of patients who recovered, deteriorated or had renalreplacement treatment. Interventions (Studies) MMF 1.5-2.0 g/d (4 studies) Control: steroids (1 study) and placebo (3 studies) Outcomes Proteinuria (4 studies) Increase in Serum Creatinine (3 studies) Need for renal replacement (3 studies) Conclusions 50% Decline Proteinuria: Total events: 61 (MMF), 38 (control) RR 1.37 (0.79, 2.38) 50% Increase in Scr: Total events: 14 (MMF), 10 (control) RR 1.19 (0.62, 2.25) Need for renal replacement therapy: Total events: 10 (MMF), 8 (control) RR: 1.10 (0.46, 2.64) Authors advice against routine use of MMF in IgAN Comments Is Eligibility criteria similar to the guideline Yes/No Yes
Are there any limitations to systematic review methodology Is limitation to evidence clearly addressed by the authors
No
Yes
Smaller number of patients Shorter duration of follow-up in a chronic disease condition Both intervention and control groups received ACE-I Studies are need to assess the effects of MMF alone or with ACE-I or ARBs Individual study quality was rated using Jadad criteria of 5 items that ranged from 3-5 No serious side-effects noted from MMF therapy. Control Steroids or placebo Outcome 50% decline in proteinuria 50% Increase in SCr N studies (N intervention group/ total N) 4 studies (89/168) 3 studies (58/106) Treatment duration Baseline kidney function/Proteinuria Pooled RR1(95% CI) 1.37 (0.79, 2.38) 18-36 mo No data available in the systematic review 1.19 (0.62, 2.25 1.10 (0.46, 2.64) P-value 0.26 0.6 0.83 Test for heterogeneity I2 P-value Statistic 75.5% 6.8% 0% 0.007 0.34 0.44
Supplementary table 59. Summary table of RCTs examining MMF in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD ESRD Frisch 2005[28] US Maes 2004[52] Belgium 2y (1 y) MMF 1000 mg 2x/d + ACE-I MMF 2 g/d, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg) MMF 2 g/d ACE-I or ARB for target BP <125/85 mmHg Placebo 1000 mg 2x/d + ACE-I Placebo lactose cap, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg) ACE-I or ARB for target BP <125/85 mmHg 17 (17) 15 (15) GFR 38 ml/min/1.73m2 2.7 g/24hr Total 100% 5 (29%) [2 (13%)] Adjusted HR 1.74 0.0742.3 NS Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) GFR/SCr Intervention Control Proteinuria Results ACE-I or ARB use Events (%) Intervention [Control] P value RR/OR/HR Quality
Cumulative % free of death or ESRD ESRD Doubling of SCr or ESRD Kidney Function SCr 50% SCr 0.5 mg/dl Inulin clearance 25% SCr 50% Proteinuria
21 (21)
13 (13)
GFR 73 ml/min/1.73 m2
1.9 g/d
Total 100%139
89% [92%] 2 (10%) [9 (45%)] 1 (5%) [3 (15%)] 3 (15%) [10 (50%)] 5 (29%) [2 (13%)]
--
NS
Fair
20 (20)
20 (20)
GFR 75 ml/min/1.73 m2
1.8 g/d
Total 100%
RR 0.22 (0.05- 0.90)140 RR 0.33 (0.04-2.94) RR 0.30 (0.10-0.93) Adjusted HR 1.62 (0.0735.6) Adjusted HR 2.84 (0.614.6) nd nd
Frisch 2005[28] US
2y (1 y)
MMF 1000 mg 2x/d + ACE-I MMF 2 g/d, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg)
Placebo 1000 mg 2x/d + ACE-I Placebo lactose cap, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg)
NS Fair NS NS Fair NS
17 (17)
15 (15)
GFR 38 ml/min/1.73m2
2.7 g/24hr
3y (3 y)
21 (21)
13 (13)
GFR 73 ml/min/1.73 m2
1.9 g/d
Total 100%141
Higher doses of ACE-I in the MMF group Calculated by ERT 141 Higher doses of ACE-I in the MMF group
139 140
Outcome
Study, Year Country Frisch 2005[28] US Tang 2005[79] Hong Kong Frisch 2005[28] US Tang 2005[79] Hong Kong
Description Intervention MMF 1000 mg 2x/d+ ACE-I MMF 2 g/d ACE-I or ARB for target BP <125/85 mmHg MMF 1000 mg 2x/d+ ACE-I MMF 2 g/d ACE-I or ARB for target BP <125/85 mmHg Control Placebo 1000 mg 2x/d + ACE-I ACE-I or ARB for target BP <125/85 mmHg Placebo 1000 mg 2x/d + ACE-I ACE-I or ARB for target BP <125/85 mmHg
No. Analyzed (Enrolled) GFR/SCr Intervention 17 (17) 20 (20) Control 15 (15) 20 (20) GFR 38 ml/min/1.73m2 GFR 75 ml/min/1.73 m2 2.7 g/24hr Proteinuria
Results ACE-I or ARB use Events (%) Intervention [Control] 3 (18%) [2 (13%)] 16 (80%) [6 (30%)] P value RR/OR/HR RR 1.32 (0.25-6.88)142 RR 2.67 (1.32-5.39)143 NS (0.739) Fair Quality
24 h protein excretion 50% Remission of proteinuria Adverse Event Treatment discontinuation MMF dose adjustment due to AE
Total 100%
1.8 g/d
Total 100%
0.006
Fair
2y (1 y) 18 mo (6 mo)
17 (17) 20 (20)
15 (15) 20 (20)
2.7 g/24hr
Total 100%
2 (11%) [2 (13%)] Anemia (n=3) Diarrhea (n=1) Infection (n=3) Discontinuation of MMF due to TB (n=1) Dose reduction due to anemia (n=2) Transient leucopenia (n=1) [Placebo pregnancy uneventful n=1 Rectal carcinoma n=1)
RR 0.88 (0.14-5.52)144
NS (0.894)
Fair
1.8 g/d
Total 100%
--
nd
Fair
Adverse event
3y (3 y)
21 (21)
13 (13)
GFR 73 ml/min/1.73 m2
1.9 g/d
Total 100%145
--
nd
Fair
Calculated by ERT Calculated by ERT 144 Calculated by ERT 145 Higher doses of ACE-I in the MMF group
142 143
Supplementary table 60. Summary table of RCTs examining MMF in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria Mean urine protein loss Tang 2005 2010[79;80] Hong Kong 18 mo (6 mo) 2y - 6 y (6 mo) MMF 2 g/d ACE-I or ARB for target BP <125/85 mmHg MMF 2 g/d, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg) MMF 2 g/d, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg) MMF 2 g/d ACE-I or ARB for target BP <125/85 mmHg ACE-I or ARB for target BP <125/85 mmHg Placebo lactose cap, (<5 g NaCl/d), ACE-I(aimed BP 125/75 mmHg) Placebo lactose cap, (<5 g NaCl/d), ACE-I (aimed BP 125/75 mmHg) ACE-I or ARB for target BP <125/85 mmHg 20 (20) 20 (20) GFR 75 ml/min/1.73 m2 1.8 g/d Total 100% 1.8 (1.87) g/d 1.8 (1.87) -0.66 (+0.53) nd 0.009 NS Fair Poor Study, Yea r Country Duration Outcome measuremen t (Treatment) Description Intervention Control No. Analyzed (Enrolled) Interventio n GFR/SCr Control Proteinuria ACE-I or ARB use Results Units Baseline Intervention (Control) Intervention (Control) P value Quality
Proteinuri a
3y (3 y)
21 (21)
13 (13)
GFR 73 ml/min/1.73 m2
1.9 g/d
Total 100%
146
g/d
1.9 1.3
-0.3 (-0.3)
NS
Fair
SCr/GFR/CrCl Annualized median Maes SCr 2004[52] Belgium Inulin clearance Annual rates of SCr Annual rates of CrCl
3y (3 y)
21 (21)
13 (13)
GFR 73 ml/min/1.73 m2
1.9 g/d
Total 100%
147
+0.11 (+0.05) -13 (-2) -0.013 (+0.108) -3.76 (-1.0) -1.125 (-3.812)
20 (20)
20 (20)
GFR 75 ml/min/1.73 m2
1.8 g/d
Total 100%
ml/min/1. 73 m2
146 147
Higher doses of ACE-I in the MMF group Higher doses of ACE-I in the MMF group
Supplementary table 61. Evidence profile of RCTs examining omega-3 fatty acid treatment in IgA nephropathy
Outcome Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney Function (continuous) Adverse events # of studies and study design 0 RCTs 2 RCTs (High) 0 RCTs 0 RCTs 1 RCT (High) 3 RCTs (High) 5 RCTs (High) 6 RCTs (High) 0 RCTs Total N (treatment) -134 (69) --30 (15) 193 (99) 240 (127) 277 (144) -Methodological quality of studies per outcome -Some limitations (-1) --Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) -Consistency across studies -No important inconsistencies (0) --N/A Important inconsistencies (-1) No important inconsistencies (0) Important inconsistencies (-1) -Directness of the evidence generalizability/ applicability* -Some uncertainty (-1) --Some uncertainty (-1) Some uncertainty (-1) Some uncertainty (-1) Some uncertainty (-1) -Summary of findings Other considerations Quality of evidence for outcome -None (0) --Sparse (-1) None (0) None (0) None (0) --Low --Very low Very low Low Very low -Qualitative and quantitative description of effect -Benefit of purified omega-3 fatty acid --Benefit of purified omega-3 fatty acid Possible benefit of omega-3 fatty acid Possible benefit of omega-3 fatty acid Possible benefit of omega-3 fatty acid -Importance of outcome Critical Critical High High High High Moderate Moderate Moderate
* Generalizability was evaluated with regard to optimized therapy of proteinuria and hypertension with angiotensin converting enzyme (ACE-I) or angiotensin receptor blockage (ARB)
Supplementary table 62. Meta-analyses and systematic reviews on fish oil treatment in IgA nephropathy
Study, Year, RefID Strippoli 2003[76] Database: Medline, EMBASE, Cochrane Renal Registry Search Dates: Until 2002 N Studies: Total 10 Fish oil 3 N Subjects: Fish oil 87 Study Eligibility Criteria RCTs and quasi RCTs evaluating the effects of different treatment regimens for IgA nephropathy on kidney function and proteinuria Interventions (Studies) Fish oil (3 studies) Outcomes Deterioration in kidney function: 50% increase in serum creatinine level from baseline value or serum creatinine level >1.5 mg/dl [132.6 mol/l] at end of treatment or reaching ESRD requiring dialysis therapy or transplantation at any time during treatment Daily proteinuria: grams of protein per 24 hours Conclusions Fish oils are not beneficial in IgA nephropathy. Comments Is Eligibility criteria similar to the guideline Yes/No yes
no
yes
Suboptimal reporting of quality of individual trials Language restrictions may have limited the results Description of limitations of evidence by authors Inclusion of RCTs and peer reviewed publication may have led to conclusions contrary to the evidence based recommendations published in 1997, and 1999. Only data for the fish oil intervention is extracted. For steroids and Immunosuppressive agents, more recent/comprehensive review by Samuels 2004 is selected. N studies (N intervention group/ total N) 2 (60/120) 3 (47/92) Weighted mean Follow-up Baseline kidney function/Proteinuria Pooled RR1(95% CI) Test for heterogeneity I2 P-value Statistic nd nd 0.09 0.01
P-value NS NS
1 study: normal or 0.63 (0.30, 1.31) impaired SCr (but <4.0 mg/dl) or Study Years : until WMD 0.12 Fish oil SCr absence and 2002 (0.50, 0.25) presence of proteinuria 20.7 mo 1 study: SCr <3.0 mg/dl or daily None/ corn oil/ 2 WMD 0.57 Fish oil Proteinuria proteinuria >1 g olive oil (Total 137) (1.59, 1.45) 1 study: Daily proteinuria >0.5 g Only data for the fish oil intervention is extracted. For steroids and Immunosuppressive agents, more recent/comprehensive review by Samuels 2004 is selected.
NS
nd
0.09
Supplementary table 63. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD ESRD Alexopoulos 2004[2] Greece Donadio 1994[20] Multicenter 4y (4 y) Purified omega-3 fatty acids 3g/d Fish oil 12 g, ACE-I for target BP 140/85 mmHg Purified omega-3 fatty acids 3 g/d, ramipril 10 mg/d, irbesartan 300 mg/d Purified omega-3 fatty acids 3 g/d Fish oil 4 g/d Fish oil 12 g, ACE-I for target BP 140/85 mmHg Supportive therapy (not described) Olive oil ACE-I for target BP 140/85 mmHg 14 (18) 14 (16) SCr 2.2 mg/dl GFR 48 ml/min GFR 82 ml/min/1.73m2 SCr 1.4 mg/dl 2.0 g/d 61% [31%] 1 (7%) [6 (43%)] RR 0.15 (0.02-1.10)148 RR 0.33 (0.130.85)149 RR 0.92 (0.62-1.36)150 RR 4.0 (1.4-11.3) NS (0.062) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria ACE-I or ARB use Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Cumulative % of death or ESRD Proteinuria %Proteinuria Proteinuria 50% Kidney Function SCr >50% GFR <50% CrCl <60% CrCl <60% SUBGROUP Scr 50%
2y (2 y)
55 (55)
51 (51)
2.5 g/d
Total 61%
0.022
Fair
6 mo (6 mo)
11 (73%) [2 (11%)] 15 (15) 15 (15) GFR 91 ml/min 1.3 g/d Total 100% 12 (80%) [3 (20%)]
NS (0.667) 0.002
Fair
Fair
Alexopoulos 2004[2] Greece Hogg 2006[35] US, Canada Donadio 1994[20] Multicenter
4y (4 y) 3y (2 y)
Supportive therapy (not described) Placebo Olive oil ACE-I for target BP 140/85 mmHg
SCr 2.2 mg/dl GFR 48 ml/min GFR 109 ml/min/1.73 m2 nd GFR 82 ml/min/1.73m2 SCr 1.4 mg/dl
1 (7%) [6[43%]] 1 (7%) [7 (50%)] 8 (19%) [4 (9%)] 6 (24%) [2 (16%)] 3 (6%) [14 (33%)]
RR 0.15 (0.02-1.10)151 RR 0.13 (0.02-0.92)152 HR 1.3 (0.4, 4.5) RR 1.70 (0.40-7.22)153 RR 0.20 (0.06-0.65)154
2y (2 y)
2.5 g/d
Total 61%
Fair
Calculated by ERT Calculated by ERT 150 Calculated by ERT 151 Calculated by ERT 152 Calculated by ERT 153 Calculated by ERT 154 Calculated by ERT
148 149
Supplementary table 64. Summary table of RCTs examining omega-3 fatty acids in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria Proteinuria Annual proteinuira Alexopoulos 2004[2] Greece 4y (4 y) Purified omega-3 fatty acids 3 g/d Purified omega-3 fatty acids 3 g/d, ramipril 10 mg/d, irbesartan 300 mg/d Fish oil 4 g/d Fish oil 12 g, ACE-I for target BP 140/85 mmHg Fish oil 6 g Supportive therapy (not described) Ramipril 10 mg/d, irbesartan 300 mg/d 14 (18) 14 (16) SCr 2.2 mg/dl GFR 48 ml/min 2.0 g/d 61% [31%] g/d 2.0 (1.6) 2.0 (1.6) -1.2 (-0.7) -0.70 [-0.19] nd <0.04 Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Interventio n Control No. Analyzed (Enrolled) Interventio n GFR/SCr Control Proteinuria Results ACE-I or ARB use Units Baseline Intervention (Control) Intervention (Control) P value Quality
UPE
Ferraro 2009[25] Italy Hogg 2006[35] US, Canada Donadio 1994[20] Multicenter Pettersson, 1994[61] Sweden
6 mo (6 mo)
15 (15)
15 (15)
GFR 91 ml/min
1.3 g/d
Total 100%
g/d
1.3 (1.5)
-9.4 (-0.9)
<.001
Fair
2y (2 y) 2y (2 y)
Placebo Olive oil ACE-I for target BP 140/85 mmHg Corn oil 6 g
30 (30) 55 (55)
29 (29) 51 (51)
GFR 109 ml/min/1.7 3 m2 GFR 82 ml/min/1.7 3m2 SCr 1.4 mg/dl Cr-EDTA 63 ml/min/1.7 3m2
2.1 g/d
53% [48%]
--
nd
NS (0.10)
Poor
2.5 g/d
Total 61%
g/d
NS
Fair
Proteinuria
6 mo (6 mo)
15 (15)
17 (17)
1.8 g/d
40% [59%]
g/d
NS
Fair
Kidney Function SCr Annual SCr GFR Annual GFR Ferraro 2009[25] Italy Hogg 2006[35] US, Canada Purified omega-3 fatty Ramipril 10 acids 3 g/d, mg/d, ramipril 10 irbesartan mg/d, 300 mg/d irbesartan 300 mg/d Fish oil 4 g/d Placebo Alexopoulos 2004[2] Greece 4y (4 y) Purified omega-3 fatty acids 3 g/d Supportive therapy (not described) 14 (18) 14 (16) SCr 2.2 mg/dl GFR 48 ml/min mg/dl 2.0 g/d 61% [31%] ml/min nd <0.01 nd <0.001 Fair Fair Fair Fair
eGFR
6 mo (6 mo)
15 (15)
15 (15)
GFR 91 ml/min
1.3 g/d
Total 100%
ml/min
91 (73)
+3.3 (-5.1)
NS (0.1)
Fair
SCr
2y (2 y)
30 (30)
29 (29)
2.1 g/d
53% [48%]
mg/dl
0.9 (0.8)
0 +0.2 +0.3
nd
Poor
Outcome
Description Interventio n Fish oil 10g/d Fish oil 12 g, ACE-I for target BP 140/85 mmHg Control No fish oil Olive oil ACE-I for target BP 140/85 mmHg Corn oil 6 g
No. Analyzed (Enrolled) Interventio n 17 (17) 55 (55) GFR/SCr Control 20 (20) 51 (51) SCr 0.09 0.2 mmol/l GFR 82 ml/min/1.7 3m2 SCr 1.4 mg/dl Cr-EDTA 63 ml/min/1.7 3m2 1.3 2.5 g/d Proteinuria
Results ACE-I or ARB use Units ml/min mg/dl 2.5 g/d Total 61% ml/min/ 1.73m2 mol/l 1.8g/d 40% [59%] ml/min ml/min/ 1.73m2 Baseline Intervention (Control) 80 76 1.4 (1.5) 82 (81) 131 (120) 91 (99) 63 (59) Intervention (Control) -23 (-21) +0.03 (+0.14) -0.3 (-7.1) +8 (+1) -12 (0) -4 (-1) P value Quality
CrCl Annual median SCr Annual median CrCl SCr CrCl Annual rate GFR
nd
nd 0.001
Poor
6 mo (6 mo)
Fish oil 6 g
15 (15)
17 (17)
Supplementary table 65. Meta-analyses and systematic reviews on antiplatelet therapy for IgA nephropathy
Study, Year Taji 2006[78] Database: Medline, Cochrane, EMBASE, Ityu-shi (Japanese medical database) Search Dates: 1970-2005 N Studies: 7 N Subjects: 458 Study Eligibility Criteria Included: Studies of antiplatelet intervention with a concurrent control group, Human adults, prospective studies. Studies that used cytotoxic agents or steroids in both arms were included. Excluded: Studies that did not clearly report data on the number of patients, dialysis population, and those with cytotoxic agents or steroids in only one arm. Interventions (Studies) Dipyridamole (5) Dilazep (1) Aspirin (1 study included both dipyridamole and aspirin) Trimetazidine dihydrochloride (1) Outcomes Level of proteinuria Renal function (introduction of RRT, creatinine clearance, serum creatinine) Side effects Conclusions Antiplatelet agents resulted in reduced proteinuria and protected renal function in patients with IgA nephropathy. Headache was reported in the dipyridamole group in one study. Comments Is eligibility criteria similar to the guideline Yes/No No (we only include only RCTs for this topic)
Yes
Is limitation to evidence clearly addressed by the authors Suboptimal quality of individual controlled trials Most studies did not assess true outcome of renal death Long-term follow-up studies may yield different set of results The effect of antiplatelet agents alone could not be discerned because patients received other concomitant therapies. Control Outcome Baseline Kidney function/Proteinuria Pooled RR1(95% CI) 0.61 (0.39, 0.94) 2 studies: Moderate to severe stage (lab or biopsy diagnosis) 5 studies: Either UPE in the range of 1.1-2.0 g/d Or CCr 51-88 ml/min 0.74 (0.63, 0.87) ARR 0.26 NNT 3.9 ARR 0.18 NNT 5.4 0.50 (0.36, 0.69) 0.69 (0.52, 0.92) 0.0 0.01 nd nd P-value 0.03 0.0
Yes
N studies Mean Follow(N intervention up group/ total N) Any antiplatelet Placebo/no 5 Taji 2006 [78] Proteinuria (218/399) therapy treatment/carbazochrome Study Years : 1970Any antiplatelet Placebo/no 6 Renal function 2005 therapy treatment/carbazochrome (161/261) Any antiplatelet Placebo/no 5 Proteinuria (218/399) therapy treatment/carbazochrome 6-60 mo* Any antiplatelet Placebo/no 6 Renal function (161/261) therapy treatment/carbazochrome Placebo/no 3 Dipyridamole Proteinuria (92/182) treatment/carbazochrome Placebo/no 4 Dipyridamole Renal function (75/155) treatment/carbazochrome * Except for Yagami 1986 Tokai J Exp Clin Med, studies had a range 6-60 mo follow-up. Yagami 1986 had 3.4 mo follow-up Author, Year, RefID Intervention
NS 0.1
Supplementary table 66. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome ESRD ESRD Walker 1990[83] Australia 5y (2 y) Cyclophosphamide 1-2 mg/kg/d, dipyridamole 400 mg/d, warfarin No treatment 25 (25) 27 (27) SCr 0.10 mmol/l 1.67 g/d 1 (4%) [2 (7%)] Amenorrhea (n=1) Oligospermia (n=1) Hematuria (n=1) Hemiplegic migrainous episode (n=1) RR 0.54 (0.055.59)155 NS (0.605) Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
In treatment group
5y (2 y)
No treatment
25 (25)
27 (27)
1.67 g/d
--
nd
Fair
155
Calculated by ERT
Supplementary table 67. Summary table of RCT examining immunosuppression and anti-platelets in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria UPE SCr/GFR/CrCl SCr Walker 1990[83] Australia 5y (2 y) Cyclophospham ide 1-2 mg/kg/d, dipyridamole 400 mg/d, warfarin No treatment 25 (25) 27 (27) SCr 0.10 mmol/l 1.67 g/d mmol/l 0.10 (0.12) +.02 (+.01) nd Fair Walker 1990[83] Australia 5y (2 y) Cyclophospham ide 1-2 mg/kg/d, dipyridamole 400 mg/d, warfarin No treatment 25 (25) 27 (27) SCr 0.10 mmol/l 1.67 g/d g/d 1.67 (1.76) -0.53 (+0.13) nd Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 68. Summary table of RCT examining antiplatelet treatments in biopsy-proven IgA nephropathy (continuous outcomes)*
Outcome SCr/GFR/CrCl Slope 1/cr v time plots Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) -0.088 (0.001) 0.125 (0.13) 77 (73) Intervention (Control) -0.008 (+0.0007) +0.073 (+0.069) +1 (-1) P value Quality
Slow release aspirin 650 Chan Vitamin ~3 y mg/d, SCr 1987[9] B (nd) dipyridamole Hong Kong complex 25-75 mg CrCl 3x/d * Based on discussions with WGM, the only Medline indexed study was data extracted.
NS NS NS Fair
Supplementary table 69. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (categorical outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) 2y (2 y) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] 21 (46%) [5 (10%)] RR 4.38 (1.8010.65)156 P value Quality
Partial remission Patients Yoshikawa showing 1997[91] normal urine Japan Proteinuria Urine protein 50% Chen 2004[13] China
Sairei-to Urokinase 100,000 IU i.v. 10 d/mo, benazepril 10 mg/d Urokinase 100,000 IU i.v. 10 d/mob benazepril 10 mg/d
Control
46 (50)
48 (51)
0.39 g/d
<0.001
Fair
1y (1 y)
Benazepril 10 mg/d
35 (35)
36 (36)
1.82 g/d
RR1.6 (1.05-2.45)157
0.027
Fair
Kidney function SCr 50% Chen 2004[13] China 1y (1 y) Benazepril 10 mg/d 35 (35) 36 (36) SCr 107 mol/l 1.82 g/d 0 (0%) [3 (8%)] -nd Fair
156 157
Supplementary table 70. Summary table of RCTs examining miscellaneous treatments in biopsy-proven IgA nephropathy (continuous outcomes)
Outcome Proteinuria Urine protein Urinary protein Chen 2004[13] China Kano 2003[45] Japan Frasca 1997[27] Italy 1y (1 y) 1y (1 y) 2y (2 y) Urokinase 100,000 IU i.v. 10 d/mo, benazepril 10 mg/d Fluvastatin 20 mg, dipyridamole 5 mg/kg Defibrotide 10mg/kg/d, prednisolone 0.5 mg/kg/alternate day Urokinase 100,000 IU i.v. 10 d/mo, benazepril 10 mg/d Fluvastatin 20 mg, dipyridamole 5 mg/kg Defibrotide 10mg/kg/d, prednisolone 0.5 mg/kg/alternate day Benazepril 10 mg/d Dipyridamol e 5 mg/kg Prednisolon e 0.5 mg/kg/altern ate day 35 (35) 15 (15) 10 (10) 36 (36) 15 (15) 10 (10) SCr 107 mol/l GFR 108 ml/min/1.73 m2 SCr 47 mol/l GFR 56 ml/min SCr 1.84 mg/dl 1.82 g/d 1.3 g/24 h/1.73 m2 1.0 g/d g/24h 1.82 (1.79) 1.3 (1.2) 1.0 (0.7) -1.20 (-0.50) -0.2 (+0.1) -0.6 (+0.2) <0.05 Fair Study, Year Country Duration Outcome measuremen t (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
g/24 h/1. 73 m2
NS
Fair
g/d
0.02
Poor
ml/min Benazepril 10 mg/d 35 (35) 36 (36) SCr 107 mol/l 1.82 g/d mol/l GFR 108 ml/min/1.73 m2 SCr 47 mol/l GFR 56 ml/min SCr 1.84 mg/dl 1.3 g/24 h/1.73 m2 ml/min/1 .73 m2 mol/l ml/min/1 .73m2 1.0 g/d mg/dl
1y (1 y)
78.9 (81.6) 107 (112) 107.9 (113.2) 46.9 (45.1) 56 (64) 1.8 (1.7)
+2.9 (-10.0) -1.0 (+33.3) +25.2 (-2.7) -5.4 (+3.5) +14% (-12%) -14% (+9%)
1y (1 y)
15 (15)
15 (15)
2y (2 y)
10 (10)
10 (10)
Supplementary table 71. Evidence profile of RCTs of MMF vs. Cyc for induction therapy in lupus nephritis
Outcome # of studies and study design 5 RCTs (High) 2 RCTs (High) 6 RCTs (High) 1 RCT (High) 0 RCTs 0 RCTs 4 RCTs (High) 4 RCTs (High) 6 RCTs (High) Total N (treatment) 618 (307) 184 (90) 683 (340) 140 (71) --152 (123) 152 (123) 683 (340) Methodological quality of studies per outcome Some limitations (-1) Some limitations (-1) Some limitations (-1) No limitations (0) --Some limitations (-1) Some limitations (-1) Consistency across studies No important inconsistencies (0) No important inconsistencies (0) Important inconsistencies (-1) NA --No important inconsistencies/ (0) No important inconsistencies (0) Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) Direct (0) --Direct (0) Direct (0) Summary of findings Other considerations Quality of evidence for outcome None (0) Imprecision (-1) None (0) Sparse (-1) --None (0) None (0) Moderate Low Low Moderate --Moderate Moderate Qualitative and quantitative description of effect No difference No difference Possible benefit for MMF158 No difference --No difference No difference More alopecia and infections with cyclophosphamide. Importance of outcome Critical Critical High High High High Moderate Moderate Moderate
Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
158
Four of the 6 trials showed no benefit with MMF for complete remission when used for induction therapy. Two trials show increased probability of complete remission with MMF. Three of the 4 trials did not show a benefit with MMF for partial remission when used for induction therapy. One trial showed MMF is more likely to induce partial remission.
Supplementary table 72. Summary table of RCTs examining MMF vs. i.v. Cyc for induction therapy in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Death Death Appel 2009[3] Multicenter Wang 2007[85] China Ginzler 2005[29] US Ong 2005[60] Malaysia El-Shafey 2010[24] Egypt Ginzler 2005[29] US Ong 2005[60] Malaysia Appel 2009[3] Multicenter Wang 2007[85] China 6 mo (6 mo) 6 mo (6 mo) 6 mo (6 mo) 36 mo (6 mo) 6 mo (6 mo) 36 mo (6 mo) 6 mo (6 mo) MMF i.v. Cyc MMF MMF i.v. Cyc i.v. Cyc 184 (185) 9 (9) 71 (71) 180 (185) 11 (11) 69 (69) SCr 1.1 mg/dl SCr 1.65 mg/dl 4.1 g/d 4.7 g/24h White 40% Asian 33% Other 27% nd Black 61% White 17% Hispanic 14% Asian 8% Malaysian 42% Chinese 53% Indian 5% Egyptian 100% Black 61% White 17% Hispanic 14% Asian 8% Malaysian 42% Chinese 53% Indian 5% White 40% Asian 33% Other 27% 9 (5%) [5 (3%)] 0 (0%) [0 (0%)] 4 (6%) [8 (3%)] 4 (6%) [8 (11%)] 0 (0%) [0 (0%)] 1 (6%) [1 (6%)] 0 (0%) [1 (4%)] RR 1.76 (0.605.15)159 -RR 0.49 (0.15-1.54)
160
P value
Quality
NS (0.29) NS nd nd NS NS (0.88) nd
Death
MMF
i.v. Cyc
4.1 g/d
Death
19 (26) 24 (24)
25 (28) 23 (23)
SCr 96.5 mol/l GFR 97 ml/min SCr 132 mol/l GFR 73.8 ml/min
1.8 g/d
MMF
i.v. Cyc
1.98.g/d
--
MMF
i.v. Cyc
4.1 g/24h
4 (6%) [7 (10%)] 1 (4%) [0 (0%)] 16 (9%) [15 (8%)] 4 (44%) [0 (0%)] 4 (44%) [0 (0%)] 2 (22%) [3 (27%)]
nd
Fair
ESRD Remission Complete remission Complete remission Partial remission Partial remission
159 160
MMF
i.v. Cyc
1.8 g/d
nd
Fair
MMF
i.v. Cyc
4.1 g/d
nd 0.026 0.026 nd
MMF
i.v. Cyc
9 (9)
11 (11)
4.70 g/24h
nd
Calculated by ERT Calculated by ERT 161 Calculated by ERT 162 Calculated by ERT 163 Calculated by ERT
Outcome Complete remission Partial remission Complete remission Complete remission Partial remission Complete remission Partial remission Relapse First renal flare after induction therapy Adverse Events Infections GI disorders Alopecia Severe infections
Study, Year Country Chan 2005[12] China Ong 2005[60] Malaysia Ginzler 2005[29] US
MMF
Cyc
32 (33) 19 (26)
30 (31) 25 (28)
SCr 1.28 mg/dl GFR 72 ml/min SCr 96.5 mol/l GFR 97 ml/min
5.32 g/24h
nd Malaysian 42% Chinese 53% Indian 5% Black 61% White 17% Hispanic 14% Asian 8%
Results Events (%) Intervention RR/OR/HR [Control] RR 0.98 24 (73%) (0.74-1.30) [23 (74%)] 164 24% [23%] -RR 2.19 (0.60-8.06)
165
P value
Quality
MMF
i.v. Cyc
1.8 g/d
RR 3.89 (1.37-11.05)
166
6 mo (6 mo)
MMF
i.v. Cyc
71 (71)
69 (69)
4.1g/d
RR 1.20 (0.69-2.07)
167
6 mo (6 mo)
MMF
i.v. Cyc
24 (24)
23 (23)
RR 1.15 (0.41-3.25)
168
1.98.g/d
Egyptian 100% 8 (33%) (7 (30%)] Black 61% White 17% Hispanic 14% Asian 8%
RR 1.10 (0.47-2.35)
169
Ginzler 2005[29] US
36 mo (6 mo)
MMF
i.v. Cyc
71 (71)
69 (69)
4.1 g/24h
8 (11%) [8 (11%)] 126 (69%) [111 (62%)] 61% [67%] 20 (11%) [64 (40%)] 1 (1%) [6 (9%)]
RR 0.98 (0.37-2.61)
nd
Fair
NS (0.17) nd nd nd
6 mo (6 mo)
MMF
i.v. Cyc
185 (185)
185 (185)
4.1 g/d
White 40% Asian 33% Other 27% Black 61% White 17% Hispanic 14%
6 mo (6 mo)
MMF
i.v. Cyc
71 (71)
69 (69)
4.1 g/d
RR 0.16 (0.02-1.31)
171
Calculated by ERT Calculated by ERT 166 Calculated by ERT 167 Calculated by ERT 168 Calculated by ERT 169 Calculated by ERT 170 Calculated by ERT 171 Calculated by ERT
164 165
Outcome Pyogenic infections Amenorrhea Alopecia Lymphopenia Leukopenia Oligomenorrhea Pneumonia/ septicemia GI AE, episodes/pt. mo Herpes zoster Leukopenia GI symptoms Elevated LFTs GI symptoms Infection Leukopenia Severe infections
Results Events (%) Intervention RR/OR/HR [Control] nd 0 (0%) [2 (3%)] 0 (0%) [8 (11%)] 18 (22%) [28 (37%)] 37% [52%] 0 (0%) [1 (4%)] 3 (16%) [3 (12%)] 0.08 [0.07] 1 (11%) [7 (64%)] RR 0.36 --RR 0.62 (0.38-1.02)
172
Quality Good Good Good Good Fair Fair Fair Fair Poor Poor Poor Poor Poor Poor Poor Good
6 mo (6 mo)
MMF
i.v. Cyc
19 (26)
25 (28)
1.8 g/d
6 mo (6 mo)
MMF
i.v. Cyc
9 (9)
11 (11)
4.70 g/24h
nd
Hu 2002[40] China
6 mo ( 6 mo)
MMF
Cyc
23 (23)
23 (23)
3.88 g/d
nd
RR 0.57 (0.19-1.69)
175
6 mo (6 mo)
MMF
i.v. Cyc
24 (24)
23 (23)
1.98.g/d
Egyptian 100%
2 (8%) [2 (9%)]
Calculated by ERT Calculated by ERT 174 Calculated by ERT 175 Calculated by ERT 176 Calculated by ERT
172 173
Outcome
Leukopenia Diarrhea
Results Events (%) Intervention RR/OR/HR [Control] RR 1.28 4 (17%) (0.32[3 (13%)] 5.10)177 RR 2.40 5 (21%) (0.52[2 (9%)] 11.14)178
P value
Quality
177 178
Supplementary table 73. Summary table of RCTs examining MMF vs. i.v. Cyc for induction therapy in patients with lupus nephritis (continuous outcomes)
Outcome Proteinuria Proteinuria Wang 2007[85] China Ginzler 2005[29] US Ong 2005[60] Malaysia El-Shafey 2010[24] Egypt Wang 2007[85] China Ginzler 2005[29] US Ong 2005[60] Malaysia El-Shafey 2010[24] Egypt 6 mo (6 mo) 6 mo (6 mo) MMF i.v. Cyc 9 (9) 71 (71) 11 (11) 69 (69) SCr 1.65 mg/dl 4.70 g/24h nd g/24h 4.7 (3.6) 4.1 (4.4) 1.35 (2.2) 2.03 (1.46) 0.001 Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Urine protein
MMF
i.v. Cyc
4.1 g/24h
Proteinuria
MMF
i.v. Cyc
SCr 96.5 mol/l GFR 97 ml/min SCr 132 mol/l GFR 73.8 ml/min
1.8 g/24h
Black 61% White 17% Hispanic g/24 h 14% Asian 8% Malaysian 42% g/24h Chinese 53% Indian 5% Egyptian 100% g/d
nd
Fair
0.04 NS (0.82)
Fair
MMF
i.v. Cyc
1.98.g/d
Good
MMF
i.v. Cyc
4.70 g/24h
nd
mg/dl
NS
Poor
SCr
MMF
i.v. Cyc
4.1 g/24h
SCr
6 mo (6 mo) 6 mo (6 mo)
MMF
i.v. Cyc
19 (26) 24 (24)
25 (28) 23 (23)
SCr 96.5 mol/l GFR 97 ml/min SCr 132 mol/l GFR 73.8 ml/min
1.8 g/d
Black 61% White 17% Hispanic mg/dl 14% Asian 8% Malaysian 42% mol/l Chinese 53% Indian 5% Egyptian 100% ml/min
nd
Fair
NS NS (0.16)
Fair
eGFR
MMF
i.v. Cyc
1.98.g/d
Good
Supplementary table 74. Existing systematic review on Cyc vs. AZA for induction treatment in patients with lupus nephritis
Study, Year, RefID Flanc 2004[26] Date Base: Cochrane Central Register of Controlled Trials 2. Medline and preMedline 3. Embase Search Dates: CENTRAL issue 2, 2003 1966 -2003 1980- 2003 N Studies: 25 1. N Subjects: 915 Study Eligibility Criteria RCTs and quasi-RCTs comparing treatments for proliferative lupus nephritis in both adult and pediatric patients with biopsy proven Class III, IV, Vc, Vd lupus nephritis were included. All treatments were considered. Outcomes Conclusions Comments Yes/No Yes, included Dichotomous: Induction with Cyclophosphamide Is eligibility 1. All cause mortality; and steroids is probably an criteria similar RCTs 2. ESRD (need for RRT) acceptable therapy as there is to the guideline 3. Doubling of Scr more data on cyclophosphamide 4. Stable renal function - <20% as an induction agent. Lack of worsening of Scr data on other agents and the lack of direct comparison of 5. Deterioration of renal function azathioprine to >20% worsening of Scr cyclophosphamide make it 6. Relapse of LN. difficult to recommend other Toxicity: agents until further research 1. major infection rate (all cause No becomes available. Given the risk Are there any infection excluding HSV) of infertility, it is reasonable that limitations to 2. HSV infection the minimal effective cumulative systematic 3. Ovarian failure review dose of cyclophosphamide be 4. Bone toxicity ( avascular used. It is not possible to be more methodology necrosis or fracture) specic about optimal dosing 5. bladder toxicity (haemorrhagic schedules. Based on this review cystitis) plasma exchange cannot be 6. Development of malignancy. Remission of proteinuria according to recommended. Is limitation to Yes the denitions of Chan 2000: evidence complete remission: urinary protein clearly excretion <0.3g/24 h. addressed by Continuous outcomes : the authors 1. Scr (mol/l) 2. CrCl (ml/min); 3. 24 h urinary protein excretion) (g/24 h); Trial quality varied greatly amongst RCTs. The small size of many of the included trials causes this analysis to have small numbers overall. Subjects differed between studies. The severity of renal impairment and the proportion of patients with Class IV LN differed amongst trials. Whilst some RCTs had very long periods of follow-up, others were much shorter and inadequately powered to detect events. N studies (N intervention group/ total N) 1 (38/57) 1 (38/57) 1 (38/57) 1 (38/57) 1 (20/30) 1 (38/57) 1 (38/57) 1 (27/45) 1 (38/57) 1 (38/57) Test for heterogeneity Pooled OR (95% CI) 0.79 [ 0.36, 1.70 ] 0.42 [ 0.15, 1.19] 0.56 [ 0.26, 1.22 ] 1.32 [ 0.86, 2.01 ] 0.67 [ 0.18, 2.42] 1.25 [ 0.27, 5.86] 2.75 [ 0.68, 11.18] 3.33 [ 1.12, 9.88 ] 3.59 [ 0.19, 66.14 ] 0.75 [ 0.14, 4.12] P-value 0.5 0.1 0.1 0.2 0.5 0.8 0.2 0.03 0.4 0.7 I2 Statistic NA P-value NA Interventions (Studies) Trials with the following treatment options were considered: 1. corticosteroids - including prednisolone, prednisone and methyl-prednisolone 2. other immunosuppressive agents - including Azathioprine, cyclophosphamide, MMF and cyclosporine 3. plasma exchange or plasmapheresis; 4. Other agents (e.g. immunoglobulins). 5. Non-specic treatment options (e.g. antihypertensive agents)were not included in the present analysis as these do not specically relate to LN but more broadly to preventing the progression of CKD
Intervention Mortality Cyc ESRD/ Doubling of Scr Cyc Adverse events Cyc
Control AZA
Outcome All cause mortality ESRD Doubling of Scr Stable renal function Deterioration of renal function Major infection Herpes Zoster Ovarian failure Bladder toxicity Malignancy
AZA
NA
NA
AZA
NA
NA
Supplementary table 75. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Grootscholten 2006[30] Netherlands ESRD/ Doubling of Scr Death ESRD Doubling of SCr Remission Remission Relapse Renal relapse Grootscholten 2006[30] Netherlands 6y (2 y) Cyc AZA 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% 2 (4%) [10 (27%)] 2 (4%) [2 (5%)] 18 [37] 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% 3 [12] nd RR 0.15 (0.03-0.64) RR 0.74 (0.03-0.64) --RR 1.1 (0.62.0) 0.010 NS (0.758) nd Fair nd NS Fair Grootscholten 2006[30] Netherlands 2y (2 y) Cyc AZA 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% *nd nd NS Fair Grootscholten 2006[30] Netherlands 6y (2 y) Cyc AZA 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% 2 (4%) [3 (8%)] 0 (0%) [1 (3%)] 2 (4%) [6 (16%)] RR 0.49 (0.09-2.81) -RR 0.25 (0.051.15) NS (0.426) nd NS (0.075) Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Results Events (%) Intervention RR/OR/HR [Control] P value Quality
6y (2 y)
Cyc
AZA
50 (50)
37 (37)
4.3 g/24h
White 70%
Adverse events Premature 6y ovarian failure (2 y) Infection rate (events/100 patient y) Grootscholten 2006[30] Cyc AZA Herpes zoster 2y Netherlands (events/100 (2 y) patient y) Hospital admission for infections *Only Kaplan Meier curves showing cumulative incidence of partial and complete remission
Supplementary table 76. Summary table of RCT examining Cyc vs. AZA for induction treatment in patients with lupus nephritis (continuous outcomes)
Outcome Proteinuria Proteinuria SCr/GFR/CrCl SCr Grootscholten 2006[30] Netherlands 6y (2 y) Cyc AZA 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% mol/l 112 (109) 80 (86) NS Fair Grootscholten 2006[30] Netherlands 6y (2 y) Cyc AZA 50 (50) 37 (37) SCr 112 mol/l GFR 65 ml/min 4.3 g/24h White 70% g/24h 4.3 (3.2) 0.2 (0.4) NS Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Interventio n Control GFR/SCr Proteinuria Race Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 77. Summary table of RCT examining low vs. high dose i.v. Cyc in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Houssiau 2002[38], 2011[39] Europe 41 mo (3 mo low; 12 mo high) 10 y follow-up 41 mo (High dose 12 mo Low dose 3 mo) 73 mo (3 mo low; 12 mo high) 73 mo (3 mo low; 12 mo high) Low dose Cyc High dose Cyc 44 (44) 45 (46) Caucasian 84% Asian 7% Black 9% 2 (5%) [0 (0%)] 5 (12%) [2 (4%)] -RR 2.62 (0.5412.77)179 RR 0.54 (0.055.70)180 HR 0.35 (0.04-3.37) HR 2.2 (0.66-7.27) RR 0.52 (0.102.71)181 RR 1.26 (0.423.81)182 HR 1.26 (0.72-2.21) HR 0.5 RR 1.02 (0.323.29)183 RR 1.02 (0.156.94)184 nd Fair nd Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Results Events (%) RR/OR/ Intervention HR [Control] P value Quality
Death
3.03 g/dl
ESRD/ doubling of SCr ESRD 1 (2%) [2 (4%)] 1 (2%) [3 (7%)] 7 (17%) [1 (2%)] 2 (4%) [4 (9%)] 10 y follow-up 6 (14%) [5 (12%)] 41 mo (3 mo low; 12 mo high) Low dose Cyc High dose Cyc 44 (44) 45 (46) Caucasian 84% Asian 7% Black 9% 30 (71%) [22 (54%)] 7 (11%) [17 (22%)] 41 mo (3 mo low; 12 mo high) Low dose Cyc High dose Cyc 44 (44) 45 (46) SCr 1.15 mg/dl 3.03 g/dl Caucasian 84% Asian 7% Black 9% 5 (11%) [5 (11%)] 2 (4%) [2 (4%)] nd
44 (44)
45 (46)
3.03 g/dl
nd
Houssiau 2002[38] Europe Adverse events Severe infection Houssiau Leukopenia 2002[38], 2011[39] Europe Menopause Renal remission
3.03 g/dl
NS (0.36) NS (0.2) nd nd
Fair
Fair
Calculated by ERT Calculated by ERT 181 Calculated by ERT 182 Calculated by ERT 183 Calculated by ERT 184 Calculated by ERT
179 180
10 y (3 mo low; 12 mo high)
Results Events (%) RR/OR/ Intervention HR [Control] RR 1.02 1 (2%) (0.07[1 (2%)] 15.85)185 RR 6.29 6 (15%) (0.79[1 (2%)] 50.04)186 RR 0.79 3 (7%) (0.19[4 (9%)] 3.30)187
P value
Quality
nd NS (0.10) NS
Supplementary table 78. Existing systematic review on i.v. vs. p.o. Cyc treatment in patients with lupus nephritis
Study, Year, RefID Flanc 2004[26] Date Base: Cochrane Central Register of Controlled Trials 5. Medline and preMedline 6. Embase Search Dates: CENTRAL issue 2, 2003 1966 -2003 1980- 2003 N Studies: 25 4. N Subjects: 915 Study Eligibility Criteria RCTs and quasi-RCTs comparing treatments for proliferative lupus nephritis in both adult and pediatric patients with biopsy proven Class III, IV, Vc, Vd lupus nephritis were included. All treatments were considered. Outcomes Conclusions Comments Yes/No Dichotomous: Induction with Is eligibility Yes, included 7. All cause mortality; Cyclophosphamide and steroids criteria similar RCTs 8. ESRD (need for RRT) is probably an acceptable to the guideline 9. Doubling of Scr therapy as there is more data on 10. Stable renal function - <20% cyclophosphamide as an worsening of Scr induction agent. Lack of data on 11. Deterioration of renal function - other agents and the lack of >20% worsening of Scr direct comparison of azathioprine 12. Relapse of LN. to cyclophosphamide make it Toxicity: difficult to recommend other 7. major infection rate (all cause agents until further research Are there any No infection excluding HSV) becomes available. Given the limitations to 8. HSV infection risk of infertility, it is reasonable systematic 9. Ovarian failure that the minimal effective review 10. Bone toxicity ( avascular cumulative dose of methodology necrosis or fracture) cyclophosphamide be used. It is 11. bladder toxicity (haemorrhagic not possible to be more specic cystitis) about optimal dosing schedules. 12. Development of malignancy. Based on this review plasma Remission of proteinuria according to exchange cannot be Is limitation to Yes the denitions of Chan 2000: recommended. evidence complete remission: urinary protein clearly excretion <0.3g/24 h. addressed by Continuous outcomes : the authors 4. Scr (mol/l) 5. CrCl (ml/min); 6. 24 h urinary protein excretion) (g/24 h); Trial quality varied greatly amongst RCTs. The small size of many of the included trials causes this analysis to have small numbers overall. Subjects differed between studies. The severity of renal impairment and the proportion of patients with Class IV LN differed amongst trials. Whilst some RCTs had very long periods of follow-up, others were much shorter and inadequately powered to detect events. Interventions (Studies) Trials with the following treatment options were considered: 6. corticosteroids - including prednisolone, prednisone and methyl-prednisolone 7. other immunosuppressive agents - including Azathioprine, cyclophosphamide, MMF and cyclosporine 8. plasma exchange or plasmapheresis; 9. Other agents (e.g. immunoglobulins). 10. Non-specic treatment options (e.g. antihypertensive agents)were not included in the present analysis as these do not specically relate to LN but more broadly to preventing the progression of CKD
Control
Outcome
N studies (N intervention group/ total N) 1 (20/38) 1 (20/38) 1 (20/38) 1 (20/38) 1 (20/38) 1 (20/38) 1 (20/38) 1 (17/27) 1 (20/38) 1 (20/38)
p.o. Cyc
0.51 [ 0.18, 1.47 ] 0.23 [ 0.03, 1.83 ] 0.72 [ 0.23, 2.27 1.11 [ 0.77, 1.59] 0.72 [ 0.23, 2.27 ] 0.60 [ 0.11, 3.19 ] 0.75 [ 0.28, 2.04 ] 0.67 [ 0.35, 1.28 ] 0.13 [ 0.01, 2.34 ] 1.20 [ 0.31, 4.65]
0.2 0.2 0.6 0.6 0.6 0.5 0.6 0.2 0.2 0.8
i.v. Cyc
Adverse events Major infection Herpes Zoster i.v. Cyc p.o. Cyc Ovarian failure Bladder toxicity Malignancy
Supplementary table 79. Summary table of RCT examining i.v. Cyc vs. p.o. Cyc in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Death Yee 2004[87] Europe 2y (2 y) i.v. Cyc Daily p.o. Cyc + AZA 13 (13) 16 (16) nd nd White 31% Asian 8% Afro Caribbean 0% Unknown 62% White 31% Asian 8% Afro Caribbean 0% Unknown 62% 2 (15%) [1 (6%)] RR 2.46 (0.25-24.22)
188
P value
Quality
nd
Poor
RRT/ doubling of SCr Doubled SCr Dialysis Yee 2004[87] Europe 2y (2 y) i.v. Cyc Daily p.o. Cyc + AZA 13 (13) 16 (16) 0 (0%) [1 (6%)] 0 (0%) [2 (13%)] 1 (8%) [3 (19%)] 3 (23%) [1 (6%)] Yee 2004[87] Europe 2y (2 y) i.v. Cyc Daily p.o. Cyc + AZA 13 (13) 16 (16) nd nd White 31% Asian 8% Afro Caribbean 0% Unknown 62% 5 (39%) [4 (25%)] 0 (0%) [1 (6%)] 1 (8%) [0 (0%)] 1 (8%) [1 (6%)] --RR 0.41 (0.05-3.49)
189
nd
nd
Adverse Events Neutropenia Nausea vomiting Infections Hemorrhagic cystitis Malignancy Permanent amenorrhea nd nd nd nd nd nd Poor Poor Poor Poor Poor Poor
RR 3.69 (0.43-31.43)
190
RR 1.54 (0.52-4.59)
191
Calculated by ERT Calculated by ERT 190 Calculated by ERT 191 Calculated by ERT 192 Calculated by ERT
188 189
Supplementary table 80. Summary table of RCT examining CsA vs. AZA for maintenance therapy in patients with lupus nephritis (categorical outcomes)
Outcome Renal flare Proteinuric flares Nephritic flare Undetectable proteinuria Adverse events Leukopenia Infections Anemia Hypertension Hyperlipidemi a Gum hyperplasia Hypertrichosis Moroni 2006[57] Italy 4y (4 y) Cyc AZA 36 (36) 33 (33) GFR 93 ml/min SCr 0.9 mg/dl 2.8 g/24h 4 (11%) [10 (30%)] 7 (19%) [14 (42%)] 5 (14%) [5 (15%)] 7 (19%) [5 (15%)] 2 (6%) [4 (12%)] 2 (6%) [0 (0%)] 2 (6%) [0 (0%)] RR 0.37 (0.131.06)196 RR 0.46 (0.210.99)197 RR 0.92 (0.292.88)198 RR 1.28 (0.453.65)199 RR 0.46 (0.092.34)200 --nd nd nd Fair nd nd nd nd Moroni 2006[57] Italy 4y (4 y) Cyc AZA 36 (36) 33 (33) GFR 93 ml/min SCr 0.9 mg/dl 2.8 g/24h Moroni 2006[57] Italy 4y (4 y) 36 (36) 33 (33) GFR 93 ml/min SCr 0.9 mg/dl 4 (11%) [6 (18%)] 2.8 g/24h 1 (3%) [1 (3%)] 15 (42%) [5 (15%)] RR 0.61 (0.191.98)193 RR 0.92 (0.06-14.07)
194
P value
Quality
Cyc
AZA
RR 2.75 (1.12-6.73)
195
Calculated by ERT Calculated by ERT 195 Calculated by ERT 196 Calculated by ERT 197 Calculated by ERT 198 Calculated by ERT 199 Calculated by ERT 200 Calculated by ERT
193 194
0 (0%) [1 (3%)] 1 (3%) [0 (0%)] 1 (3%) [0 (0%)] 14 (39%) [3 (9%)] 11 (31%) [3 (9%)]
nd nd nd nd nd
201 202
Supplementary table 81. Summary table of RCT examining CsA vs. AZA for maintenance therapy in patients with lupus nephritis (continuous outcomes)
Outcome Proteinuria Proteinuria SCr/GFR/CrCl CrCl Moroni 2006[57] Italy 2y (2 y) 4y (4 y) Cyc AZA 36 (36) 33 (33) GFR 93 ml/min SCr 0.9 mg/dl 2.8 g/24h ml/min 92.5 (104.1) 92.5 (104.1) 82.6 (09.9) -6.9 (-5.1) 0.044 Poor NS Moroni 2006[57] Italy 2y (2 y) 4y (4 y) Cyc AZA 36 (36) 33 (33) GFR 93 ml/min SCr 0.9 mg/dl 2.8 g/24h g/d 2.8 (2.2) 2.8 (2.2) 0.38 (0.53) 0.23 (0.33) NS Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 82. Summary table of RCT examining i.v. Cyc vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Outcome Remission Remission Complete remission Austin 2009[4] US 12 mo (12 mo) 15 (15) 15 (15) GFR 83 ml/min/1.73m2 Black 64% White 29% Hispanic 7% 9 (60%) [4 (27%)] 6 (40%) [2 (13%)] 1 (8%) [2 (13%)] 0 (0%) [0 (0%)] 0 (0%) [0 (0%)] 2 (17%) [0 (0%)] 9 (75%) [0 (0%)] Austin 2009[4] US 12 mo (12 mo) Cyc Prednisone 15 (15) 15 (15) GFR 83 ml/min/1.73m2 5.4 g/d Black 64% White 29% Hispanic 7% 8 (67%) [0 (0%)] 4 (33%) [0 (0%)] 7 (58%) [4 (27%)] 2 (17%) [1 (7%)] 0 (0%) [0 (0%)] RR 2.25 (0.885.73)203 RR 3.00 (0.72-12.55)
204
P value
Quality
0.04 nd
Fair Fair
Cyc
Prednisone
5.4 g/d
ESRD/ doubling of SCr Austin Doubling of SCr 2009[4] US Adverse Events Leukopenia Amenorrhea Nausea/anorexi a BP with or without SCr Gingival hyperplasia/ facial hair Paresthesia/ tremor Infections Pneumonia Herpes zoster
12 mo (12 mo)
Cyc
Prednisone
15 (15)
15 (15)
GFR 83 ml/min/1.73m2
5.4 g/d
RR 0.50 (0.05-4.94)
205
nd
Fair
nd nd nd nd nd nd nd nd nd
RR 2.00 (0.20-19.78)
207
--
Calculated by ERT Calculated by ERT 205 Calculated by ERT 206 Calculated by ERT 207 Calculated by ERT
203 204
Outcome
Results Events (%) Intervention RR/OR/HR [Control] RR 1.67 5 (42%) (0.48-5.76) [3 (20%)] 208 2 (17%) [4 (27%)] 0 (0%) [0 (0%)] RR 0.50 (0.11-2.33)
209
P value
Quality
nd
Fair
nd nd
Fair Fair
--
208 209
Supplementary table 83. Summary table of RCT examining i.v. CsA vs. prednisone in patients with membranous lupus nephritis (categorical outcomes)
Outcome Remission Remission Complete remission Austin 2009[4] US 12 mo (12 mo) 12 (12) 15 (15) GFR 83 ml/min/1.73m2 Black 64% White 29% Hispanic 7% 10 (83%) [4 (27%)] 6 (50%) [2 (13%)] 1 (7%) [2 {13%)] 2 (13%) [0 (0%)] 0.25 (25%) [0 (0%)] 3 (20%) [0 (0%)] Austin 2009[4] US Black 64% White 29% Hispanic 7% 10 (67%) [4 (27%)] 0 (0%) [1 (7%)] 2 (13%) [0 (0%)] 8 (53%) [3 (20%)] 3 (20%) [4 (27%)] RR 3.13 (1.30-7.51)
210
P value
Quality
0.002 nd
Fair Fair
CsA
Prednisone
5.4 g/d
ESRD/ doubling of SCr Austin Doubling of SCr 2009[4] US Adverse Events Leukopenia Amenorrhea Nausea/anorexia Infections Pneumonia Herpes zoster Other Osteoporosis/ hip avascular necrosis
12 mo (12 mo)
CsA
Prednisone
12 (12)
15 (15)
GFR 83 ml/min/1.73m2
5.4 g/d
nd
Fair
nd nd nd nd nd nd nd nd
12 mo (12 mo)
CsA
Prednisone
12 (12)
15 (15)
GFR 83 ml/min/1.73m2
5.4 g/d
RR 0.94 (0.26-3.41)
215
Calculated by ERT Calculated by ERT 212 Calculated by ERT 213 Calculated by ERT 214 Calculated by ERT 215 Calculated by ERT
210 211
1 (7%) [0 (0%)]
--
nd
Fair
Supplementary table 84. Summary table of RCT CsA vs. i.v. Cyc in patients with membranous lupus nephritis (categorical outcomes)
Outcome Remission Remission Complete remission Austin 2009[4] US 12 mo (12 mo) 12 (12) 15 (15) GFR 83 ml/min/1.73m2 Black 64% White 29% Hispanic 7% 10 (83%) [9 (60%)] 6 (50%) [6 (40%)] 1 (7%) [1 (8%)] 2 [0.2] 0 (0%) [2 (13%)] 0 (0%) (1/4 (25%)] 2 (17%) [3 (20%)] Austin 2009[4] US 12 mo (12 mo) CsA Prednisone 12 (12) 15 (15) GFR 83 ml/min/1.73m2 5.4 g/d Black 64% White 29% Hispanic 7% 9 (75%) [0 (0%)] 8 (67%) [0 (0%)] 4 (33%) [0 (0%)] 7 (58%) [10 (67%)] RR 1.39 (0.862.25)216 RR 1.25 (0.54-2.89)
217
P value
Quality
nd nd
Fair Fair
CsA
Prednisone
5.4 g/d
ESRD/ doubling of SCr Austin Doubling of SCr 2009[4] US Relapse Incidence of Austin relapse/100 2009[4] patient mo US Adverse Events Leukopenia Amenorrhea Nausea/anorexia BP with/without SCr Gingival hyperplasia/ facial hair Paresthesia/ tremor Infections
CsA
Prednisone
12 (12) 12 (12)
15 (15) 15 (15)
5.4 g/d
Black 64% White 29% Hispanic 7% Black 64% White 29% Hispanic 7%
nd
Fair
CsA
Prednisone
5.4 g/d
0.02
Fair
nd nd nd nd nd nd nd
Calculated by ERT Calculated by ERT 218 Calculated by ERT 219 Calculated by ERT 220 Calculated by ERT
216 217
Outcome Pneumonia Herpes zoster Other Osteoporosis/hip avascular necrosis Basal cell skin cancer
Results Events (%) Intervention RR/OR/HR [Control] 2 (17%) -[0 (0%)] 0 (0%]) -[2 (13%)] RR 0.78 5 (42%) (0.34-1.77) [8 (53%)] 221 2 (17%) [3 (20%)] 0 (0%) [1 (7%)] RR 0.83 (0.16-4.21)
222
P value nd nd nd nd nd
--
221 222
Supplementary table 85. Summary table of RCT examining rituximab + cyclophosphamide vs. rituximab in patients with proliferative lupus nephritis (categorical outcomes)
Outcome Remission Complete response Partial response Complete or partial response Total sustained complete response Adverse events AE- Infections AE-Cramps AE-Ankle swelling AE-Insomnia AE-Pruritis AE-Dyspepsia AE-Urticaria AE-Chest pain AE-Abdominal distension AE-Depression AE-Malaise Li 2009[49] Hong Kong 48 wk (48 wk) Rituximab + Cyc Rituximab 10 (10) 9 (9) SCr 134.8 mol/l 3.8 g/24h Li 2009[49] Hong Kong 48 wk (48 wk) Rituximab + Cyc Rituximab 10 (10) 9 (9) SCr 134.8 mol/l 3.8 g/24h 2 (20%) [2 (22%)] 5 (50%) [6 (66%)] 7 (70%) [8 (88%)] 4 (21%) 5 (50%) [7 (77%)] 0 (0%) [4 (44%)] 4 (40%) [3 (33%)] 2 (20%) [0 (0%)] 2 (20%) [0 (0%)] 2 (20%) [0 (0%)] 2 (20%) [0 (0%)] 1 (10%) [0 (0%)] 1 (10%) [0 (0%)] 0 (0%) [1 (11%)] 1 (10%) [0 (0%)] RR 0.90 (0.16-5.13) 223 RR 0.75 (0.35-1.62) 224 RR 0.79 (0.49-1.26) 225 -RR 0.64 (0.32-1.31) 226 -RR 1.20 (0.36-3.97) 227 --------nd nd nd nd nd nd nd nd nd nd nd nd nd nd nd Poor Poor Poor Poor Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Calculated by ERT Calculated by ERT 225 Calculated by ERT 226 Calculated by ERT 227 Calculated by ERT
223 224
Supplementary table 86. Summary table of RCT examining rituximab + cyclophosphamide vs. rituximab in patients with proliferative lupus nephritis (continuous outcomes)
Outcome Proteinuria Proteinuria SCr/GFR/CrCl CrCl Li 2009[49] Hong Kong 48 wk (48 wk) Rituximab + Cyclophosphamide Rituximab 10 (10) 9 (9) SCr 134.8 mol/l 3.8 g/24h mol/l 64.2 (81.4) nd (nd) NS Poor Li 2009[49] Hong Kong 48 wk (48 wk) Rituximab + Cyclophosphamide Rituximab 10 (10) 9 (9) SCr 134.8 mol/l 3.8 g/24h g/24h 3.8 (4.1) nd (nd) NS Poor Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Supplementary table 87. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (categorical outcomes)
Outcome Proteinuria Daily UPE <0.3 g/24h Kidney function Maintenance of normal SCr Adverse events All infections Serious infections Hyperlipidemia Blood glucose HbA1c Nausea Hypertension Miyasaka 2009[56] Japan 28 wk (28 wk) Tacrolimus Placebo 27 (28) 33 (35) GFR 101 ml/min SCr 0.67 mg/dl 1.6 g/d 16 (57%) [20 (57%)] 2 (7%) [1 (3%)] 2 (7%) [3 (9%)] 4 (14%) [0 (0%)] 2 (7%) [0 (0%)] 4 (14%) [0 (0%)] 2 (7%) [3 (9%)] RR 0.86 (0.59-1.26) 230 RR 2.15 (0.21-22.37) 231 RR 0.72 (0.13-3.96) 232 ---RR 0.72 (0.13-3.96) 233 NS NS NS <0.05 NS <0.05 NS Fair Miyasaka 2009[56] Japan 28 wk (28 wk) Tacrolimus Placebo 27 (28) 33 (35) GFR 101 ml/min SCr 0.67 mg/dl 1.6 g/d 22 (92%) [26 (90%)] RR 1.03 (0.80-1.33) 229 NS Fair Miyasaka 2009[56] Japan 28 wk (28 wk) Tacrolimus Placebo 27 (28) 33 (35) GFR 101 ml/min SCr 0.67 mg/dl 1.6 g/d 4 (15%) [1 (3%)] RR 4.89 (0.58-41.20) 228 NS Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Calculated by ERT Calculated by ERT 230 Calculated by ERT 231 Calculated by ERT 232 Calculated by ERT 233 Calculated by ERT
228 229
Supplementary table 88. Summary table of RCT examining TAC vs. placebo in patients with lupus nephritis (continuous outcomes)
Outcome SCr/GFR/CrCl CrCl Miyasaka 2009[56] Japan 12 wk (28 wk) 28 wk (28 wk) 28 wk (28 wk) Tacrolimus Placebo 27 (28) 33 (35) GFR 101 ml/min SCr 0.67 mg/dl 1.6 g/d ml/min 101.4 [95.8] 79.1 [93.4] 78.2 [92.9] -1.8 [0.0] 0.005 Fair 0.060 Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
Disease activity Lupus nephritis Miyasaka disease activity 2009[56] index Japan
Tacrolimus
Placebo
27 (28)
33 (35)
1.6 g/d
nd
5.3 [5.2]
<0.001
Fair
Supplementary table 89. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (categorical outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) 12 wk (6 mo) TAC 24 wk (6 mo) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] 28% [16%] 50% [47%] 39% [37%] 44% [58%] 3 (17%) [2 (11%)] 1 (6%) [1 (6%)] 1 (6%) [0 (0%)] 2 (11%) [0 (0%)] 8 (44%) [0 (0%)] ----RR 1.58 (0.30-8.40) 234 RR 1.06 (0.07-15.64) 235 ---P value NS (0.5) NS (0.5) NS (0.5) NS (0.5) nd nd nd nd nd Poor Quality
Remission Complete remission Partial Szeto remission 2008[77] Complete China remission Partial remission Adverse events Infection Elevated LFTs Angioedema Tremor Dyspepsia Szeto 2008[77] China
Poor
18 (18)
19 (19)
4.57 g/d
Poor
12 wk (6 mo)
TAC
18 (18)
19 (19)
4.57 g/d
234 235
Supplementary table 90. Summary table of a study examining TAC vs. standard protocols of steroid + p.o. Cyc or AZA in patients with class V lupus (continuous outcomes)
Outcome Proteinuria Proteinuria SCr/GFR/CrCl eGFR Szeto 2008[77] China 12 wk (6 mo) TAC Standard protocols of steroid + p.o. Cyc or AZA 18 (18) 19 (19) SCr 93 mg/dl GFR 103 ml/min 4.57 g/d ml/min/1. 73m2 102.8 (103.1) nd NS (0.7) Poor Szeto 2008[77] China 12 wk (6 mo) TAC Standard protocols of steroid + p.o. Cyc or AZA 18 (18) 19 (19) SCr 93 mg/dl GFR 103 ml/min 4.57 g/d g/d 4.57 (3.62) 76% (47%) 0.03 Poor Study, Yea r Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Qualit y
Supplementary table 91. Summary table of a study examining AZA vs. i.v. Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Mortality Cumulative rate of renal survival Contreras Event-free 2004[15] survival for 2005[16] US composite end point of death or chronic renal failure236 Relapse free survival ESRD/ doubling of SCr Contreras Chronic renal 2004[15] 237 failure 2005[16] US Relapse Contreras Relapse 2004[15] 2005[16] US Adverse events Infection Amenorrhea Leukopenia Contreras 2004[15] 2005[16] US 30 mo (30 mo) AZA + steroids i.v. Cyc + steroids 19 (19) 20 (20) SCr 1.7 mg/dl 5.7 mg/mg Black 47% Hispanic 42% White 11% 30 mo (30 mo) AZA + steroids 60-72 mo (30 mo) 30 mo (30 mo) 30 mo (30 mo) 30 mo (30 mo) AZA + steroids AZA + steroids i.v. Cyc + steroids i.v. Cyc + steroids 19 (19) 19 (19) 20 (20) 20 (20) SCr 1.7 mg/dl 5.7 mg/mg Black 47% Hispanic 42% White 11% Black 47% Hispanic 42% White 11% i.v. Cyc + steroids 19 (19) 20 (20) SCr 1.7 mg/dl 5.7 mg/mg Black 47% Hispanic 42% White 11% 0 (0)% [4 (20%)] 80% [74%] nd 89% [80%] nd 1 (5)% [3 (15%)] 6 (32%) [8 (40%)] 29% [77%] 8% [32%] 6% [10%] ---0.02 nd 0.009 nd NS (0.12) nd Fair Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Results No. Events (%) RR/OR/HR Intervention [Control] P value Quality
Fair
Fair
5.7 mg/mg
RR 0.79 (0.34-1.85)
239
nd
Fair
----
236 237
ESRD, transplant or doubling of SCr from lowest value achieved during induction ESRD, transplant or doubling of SCr from lowest value achieved during induction 238 Calculated by ERT 239 Calculated by ERT
Supplementary table 92. Summary table of a study examining MMF vs. i.v. Cyc maintenance therapy in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Mortality Cumulative rate of renal survival Contreras Event-free 2004[15] survival for 2005[16] composite end US point of death or chronic renal failure241 Relapse free survival ESRD/ doubling of SCr Contreras Chronic renal 2004[15] failure242 2005[16] US Relapse Contreras 2004[15] Relapse 2005[16] US Adverse events Infection Amenorrhea Leukopenia Contreras 2004[15] 2005[16] US 29 mo (29 mo) MMF 60-72 mo (29 mo) 29 mo (29 mo) 29 mo (29 mo) i.v. Cyc + steroids 20 (20) 20 (20) Black 45% Hispanic 50% White 5% Black 45% Hispanic 50% White 5% i.v. Cyc + steroids 20 (20) 20 (20) SCr 1.6 mg/dl 4.7 mg/mg Black 45% Hispanic 50% White 5% 1 (5%) [4 (20%)] 95% [74%] nd -89% [45%] nd -RR 0.33 (0.04-2.94)
243
P value
Quality
NS (0.11) nd 0.005
Fair Fair
--
MMF
4.7 mg/mg
1 (5)% [3 (15%)]
nd
Fair
29 mo (29 mo)
MMF
20 (20)
20 (20)
4.7 mg/mg
RR 0.38 (0.12-1.21)
244
nd
Fair
29 mo (29 mo)
MMF
20 (20)
20 (20)
4.7 mg/mg
by ERT ESRD, transplant or doubling of SCr from lowest value achieved during induction 242 ESRD, transplant or doubling of SCr from lowest value achieved during induction 243 Calculated by ERT 244 Calculated by ERT
Supplementary table 93. Evidence profile of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis
Outcome # of studies and study design 3 RCTs (High) 1 RCT (High) 0 RCTs 3 RCTs (High) 0 RCTs 1 RCT (High) 1 RCT (High) 1 RCT (High) 3 RCTs (High) Total N (treatment) 156 (94) 105 (53) -206 (105) -105 (53) 62 (32) 62 (32) 206 (105) Methodological Consistency quality of studies across studies per outcome Some limitations (-1) No limitations (0) -No limitations (0) -No limitations (0) Some limitations (-1) Some limitations (-1) No important inconsistencies (0) N/A Directness of the evidence generalizability/ applicability Direct (0) Direct (0) -Direct (0) -Direct (0) Direct (0) Direct (0) Summary of findings Other considerations Imprecision (-1) Imprecision (-1) Sparse (-1) -Imprecision (-1) -Imprecision (-1) Sparse (-1) Sparse (-1) Sparse (-1) Quality of evidence for Qualitative and quantitative description of outcome effect Low No difference Importance of outcome Critical
Mortality
ESRD
Low
No difference
Critical
Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
-Moderate --
-No difference --
N/A
Low
No difference
High
N/A N/A
Low Low
Supplementary table 94. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (categorical outcomes)
Outcome Mortality Mortality Cumulative rate of renal survival Event-free survival for composite end point of death or chronic renal failure245 Relapse free survival Death 30 mo (30 mo) Contreras 2004[15] 2005[16] US 60-72 mo (30 mo) 30 mo (30 mo) Chan 2000[10] China Chan 2005[12] China Houssiau 2010[37] Europe 12 mo (12 mo) 63 mo (12 mo) 48 mo (44 mo) MMF+ prednisone MMF+ prednisone i.v. Cyc + prednisone, then AZA + prednisone i.v. Cyc + prednisone, then AZA + prednisone AZA 21 (21) 32 (33) 53 (53) 21 (21) 30 (33) 52 (52) GFR 86 ml/min SCr 1.2 mg/dl GFR 72 ml/min SCr 1.28 mg/dl SCr 1.01 mg/dl 5.8 g/24h nd MMF AZA 20 (20) 19 (19) SCr 1.7 mg/dl 4.7 mg/mg Black 45% Hispanic 50% White 5% 1 (5%) [0 (0%)] 95% [80%] --89% [80%] -0 (0%) [2 (10%)] 0 (0%) [4 (12%)] 2 (4%) [0 (0%)] ----NS (0.33) nd NS (0.50) nd NS (0.22) NS (0.49) NS (0.062) Fair Fair Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Results No. Events (%) RR/OR/HR Intervention [Control] P value Quality
Fair
Death/ESRD
5.32 g/24h
nd White 42% Black 6% Asian 5% Black 45% Hispanic 50% White 5% White 42% Black 6% Asian 5%
--
Fair
Death
MMF
3.63 g/24h
--
nd
Good
ESRD/ doubling of SCr Contreras Chronic renal 2004[15] 246 failure 2005[16] US Houssiau Doubling SCr 2010[37] Europe
245 246
MMF MMF
AZA AZA
20 (20) 53 (53)
19 (19) 52 (52)
RR 0.95 (0.06-14.13)
247
nd nd
Fair Good
RR 0.74 (0.173.13)248
ESRD, transplant or doubling of SCr from lowest value achieved during induction ESRD, transplant or doubling of SCr from lowest value achieved during induction 247 Calculated by ERT 248 Calculated by ERT
Outcome
ESRD Relapse Relapse Relapse Time to relapse, wk Relapse Time to relapse, wk Renal flare Adverse events Infection Amenorrhea Leukopenia Infection Hair loss Permanent amenorrhea Calculated by ERT Calculated by ERT 251 Calculated by ERT 252 Calculated by ERT
249 250
Results No. Events (%) RR/OR/HR Intervention [Control] RR 0.98 1 (2%) (0.061 (2%) 15.28)249 3 (15%) [6 (32%)] 3 (15%) [2 (11%)] 40 [39] RR 0.48 (0.14-1.63)
250
P value
Quality
Contreras 2004[15] 2005[16] US Chan 2000[10] China Chan 2005[12] China Houssiau 2010[37] Europe
MMF
AZA i.v. Cyc + prednisone, then AZA + prednisone i.v. Cyc + prednisone, then AZA + prednisone AZA
20 (20) 21 (21)
19 (19) 21 (21)
SCr 1.7 mg/dl GFR 86 ml/min SCr 1.2 mg/dl GFR 72 ml/min SCr 1.28 mg/dl SCr 1.01 mg/d
4.7 mg/mg
Fair
MMF+ prednisone
RR 1.50 (0.28-8.08)
251
5.8 g/24h
Fair
MMF+ prednisone
32 (33) 53 (53)
30 (33) 52 (52)
5.32 g/24h
Fair
MMF
3.63 g/24h
Good
30 mo (30 mo)
MMF
AZA
20 (20)
19 (19)
1.71.6 mg/dl
4.74.3 mg/mg
12 mo (12 mo)
MMF+ prednisone
21 (21)
21 (21)
5.8 g/24h
nd
---
Outcome
Leukopenia Diarrhea Incidence of infection Incidence of hospitalized infections Hair loss Amenorrhea Permanent amenorrhea Leukopenia GI upset Infection Leukopenia Diarrhea Houssiau 2010[37] Europe 48 mo (44 mo) MMF AZA 53 (53) 52 (52) SCr 1.01 mg/dl 3.63 g/24h White 42% Black 6% Asian 5% Chan 2005[12] China 63 mo (12 mo) MMF+ prednisone i.v. Cyc + prednisone, then AZA + prednisone 32 (33) 30 (33) GFR 72 ml/min SCr 1.28 mg/dl 5.32 g/24h nd
Results No. Events (%) RR/OR/HR Intervention [Control] 0 (0%) -[2 (10%)] 1 (5%) -[0 (0%)] 1/234 pt-mo Rate Ratio [1/102.5 pt2.28 mo] (0.96-5.43) 1/327.6 Rate Ratio pt.mo 1.85 [1/177 pt(0.64-5.33) mo] 0 (0%) -[9 (29%)] 4% -[36%] 0% -[56%] 0 (0%) -[8 (26%)] RR 2.81 3 (9%) (0.31-25.58) [1 (3%)] 253 21 (40%) [14 (27%)] 2 (4%) [11 (21%)] 8 (15%) [8 (15%)] RR 1.47 (0.842.57)254 RR 0.18 (0.040.77)255 RR 0.98 (0.402.42)256
Quality
Calculated by ERT Calculated by ERT 255 Calculated by ERT 256 Calculated by ERT
253 254
Supplementary table 95. Summary table of studies examining MMF vs. AZA maintenance therapy in patients with lupus nephritis (continuous outcomes)
Outcome Scr/GFR SCr, mg/dl Cr Cl, ml/min/1.73 m2 SCr slope CrCl slope Proteinuria Proteinuria Chan 2000[10] China Chan 2005[12] China 12 mo (12 mo) 63 mo (12 mo) MMF+ prednisone MMF+ prednisone i.v. Cyc + prednisone, then AZA + prednisone i.v. Cyc + prednisone, then AZA + prednisone 21 (21) 32 (33) 21 (21) 30 (33) GFR 86 ml/min SCr 1.2 mg/dl GFR 72 ml/min SCr 1.28 mg/dl 5.8 g/24h nd 5.8 (3.7) 6.21 (4.44) -5.3 (-3.5) -0.085 (-0.055) nd Fair Chan 2000[10] China Chan 2005[12] China 12 mo (12 mo) MMF+ prednisone i.v. Cyc + prednisone, then AZA + prednisone i.v. Cyc + prednisone, then AZA + prednisone 21 (21) 21 (21) GFR 86 ml/min SCr 1.2 mg/dl 1.13 (1.10) 5.8 g/24h nd 86 (77) 1.27 (1.28) 67.4 (74.9) -0.16 (-0.11) +6 (+5) -0.308 (0.242) 0.142 (0.057) NS nd NS (0.914) NS (0.131) Fair Fair Fair Fair Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Race Results Baseline Intervention Intervention (Control) (Control) P value Qualit y
63 mo (12 mo)
MMF+ prednisone
32 (33)
30 (33)
5.32 g/24h
nd
Proteinuriaslope
5.32 g/24h
nd
NS (0.075)
Fair
Supplementary table 96. Evidence profile of i.v. vs. p.o. Cyc for ANCA vasculitis
Outcome # of studies and study design 1 RCT (High) 1 SR (3 RCTs) 1 RCT (High) 1 SR (3 RCTs) 1 RCT (High) 1 SR (3 RCTs) 1 RCT (High) 1 SR (3 RCTs) 0 RCTs 0 RCTs 0 RCTs 1 RCT (High) 1 SR (2 RCT s) 1 RCT (High) 1 SR (3 RCTs) Total N (treatment) 149 (76) 129 (61) 149 (76) 129 (61) 149 (76) 97 (49) 149 (76) 119 (57)) ---149 (76) 52 (21) 149 (76) 129 (61) Methodological quality of studies per outcome Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) Some limitations (-1) ---Some limitations (-1) Some limitations (-1) Consistency across studies No important inconsistencies (0) No important inconsistencies (0) Important inconsistencies (-1) No important inconsistencies (0) ---No important inconsistencies (0) Directness of the evidence generalizability/ applicability Direct (0) Direct (0) Direct (0) Direct (0) ---Direct (0) Summary of findings Other considerations Quality of evidence for outcome Qualitative and quantitative description of effect Importance of outcome
Mortality
None
Moderate
Critical
RRT
None
Moderate
Critical
Remission
None
Low
High
Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
None ---None
Moderate ---Moderate
Benefit for oral cyclophosphamide ---No difference for change in kidney function
Balance of potential benefits and harm: Benefit for oral cyclophosphamide in preventing relapse
Supplementary table 97. Existing systematic review of Induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis
Study, Year, RefID Walters 2008[84] Date Base: Cochrane Central Register of Controlled Trials 2. Cochrane Renal Group Specialized Register, 3. MEDLINE EMBASE Search Dates: 1966-2008 1. N Studies: 13 N Subjects: 702 Study Eligibility Criteria All RCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at any intervention used for the treatment of renal vasculitis in adults. Inclusion criteria All adult patients suffering from an episode of AKF and/or proteinuria and hematuria with a kidney biopsy showing severe acute GN with crescents, glomerular necrosis or other histological evidence of vasculitis. AKF was as dened by the included studies. Exclusion criteria 1. RPGN with granular immune deposits such as SLE, cryoglobulinemia, HSP. 2. RPGN secondary to infections. 3. Polyarteritis nodosa. 4. Churg Strauss disease. 5. Goodpastures disease 1. 2. Interventions (Studies) Corticosteroids versus placebo. Non-corticosteroid agents, including Cyc, AZA, plasma exchange and immunoadsorption, with or without concurrent use of other immunosuppressive agents. Different doses and duration of corticosteroid treatment. Different doses, duration and route of administration of noncorticosteroid treatment Any other agents evaluated in a RCT 1. 2. 3. 4. 5. Outcomes Mortality at 1, 2 and 5 years. Kidney function: SCr) level at 1, 2, 3, 6 and 12 months then annually. Need for RRT at 1, 2, 3, 6 and 12 months then annually. No. of patients relapsing (as dened by the study). Adverse effects of each drug (e.g. nausea, leukopenia, and infections). Cumulative doses of steroid and other agents. Relapse of disease is dened by the included studies, but typically included an increase in BVAS score or a recurrence of symptoms of vasculitis. 1. Conclusions On current data, the use of pulse Cyc results in an increased risk of relapse when compared to continuous use but a reduced total dose. Comments Is eligibility criteria similar to the guideline Yes/No Yes
3. 4. 5.
6. 7.
Is limitation to evidence clearly addressed by the authors The review is limited by the small number of available studies and some design features of the included studies. Several included diagnoses other than renal vasculitis. Some date prior to the development of the ANCA assay. This will limit the validity of the data and diagnoses included in those studies. Other differences include those between interventions, notably the regimens of immunosuppressive drugs and the number and volume of plasma exchanges utilized. Some of these may have had a very signicant impact on the outcomes of studies and may explain the level of heterogeneity in some of our results
Intervention Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc
Control Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc
Outcome Death at 3 months Death at 6 months Death at 1 year Death at 2 years Death at 5 years Death at final FU Dialysis at 1 month Dialysis at 2 months Dialysis at 3 months Dialysis at 6 months Dialysis at 12months Dialysis end of study Scr at 1 month Scr at 2 months Scr at 3 months Scr at 6 months Scr at 12 months Scr at 2 years
N studies (N intervention group/ total N) 1(12/32) 1(12/32) 2(39/82) 3(61/129) 0 3(61/129) 0 0 0 1(27/50) 0 3(61/129) 0 0 1(10/28) 1(10/27) 2(21/52) 2(21/52) N studies (N intervention group/ total N) 1(27/50) 1(22/47) 2(49/97) 1(22/47) 1(22/47) 3(57/119) 2(39/82) 3(61/129) 3(61/129) 2(49/97)
Test for heterogeneity Pooled OR1(95% CI) 1.67 [ 0.27, 10.33 ] 1.11 [ 0.22, 5.73 ] 0.82 [ 0.25, 2.72] 0.75 [ 0.21, 2.61 ] 0 0.87 [ 0.42, 1.80] 0 0 0 6.00 [ 0.33, 110.43] 0 1.70 [ 0.78, 3.67 ] 0 0 -4.58 [ -97.77, 88.61 ] 51.69 [ -81.03, 184.41 ] -9.78 [ -53.16, 33.61 ] 0 P-value 0.58 0.90 0.75 0.65 NA 0.71 NA NA NA 0.23 NA 0.18 NA NA 0.92 0.45 0.66 0.90 I2 Statistic NA NA 44 56 NA 32 NA NA NA NA NA 0 NA NA NA NA 0 0 Test for heterogeneity P-value NA NA 0.18 0.11 NA 0.23 NA NA NA NA NA 0.66 NA NA NA NA 0.98 0.81
Intervention Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc Pulse Cyc
Control Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc Continuous Cyc
Outcome Remission at 6 months Untimed remission Total Relapse at 1 year Relapse at 2 years Untimed relapse Treatment failure Serious infections Leukopenia Nausea
Pooled OR1(95% CI) 1.14 [ 0.88, 1.46 ] 1.18 [ 0.98, 1.42 ] 1.17 [ 1.00, 1.35 ] 2.84 [ 0.61, 13.21 ] 1.89 [ 0.51, 7.03 ] 1.75 [ 1.00, 3.05 ] 1.36 [ 0.15, 12.56] 0.71 [ 0.32, 1.58] 0.43 [ 0.22, 0.84 ] 2.51 [ 1.07, 5.89]
P-value 0.32 0.077 0.044 0.18 0.34 0.050 0.79 0.40 0.014 0.035
I2 Statistic NA NA 0 NA NA 0 69 80 0 0
Supplementary table 98. Summary table of RCT examining the effect of induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (categorical outcomes)
Outcome Mortality Death de Groot 2009[18] EU/Mexico 6 mo (6 mo) Pulse Cyc Daily p.o. Cyc 76 (76) 73 (73) SCr 225 mol/l/ SCr 2.55 mg/dl GFR 38 ml/min/1.73 m2 SCr 225 mol/l/ SCr 2.55 mg/dl GFR 38 ml/min/1.73 m2 nd 5 (7%) [9 (2%)] RR 0.53 (0.19-1.52)
257
P value
Quality
NS (0.79)
Fair
RRT/ Doubling of Scr ESRD Remission 3 mo (6 mo) 6 mo (6 mo) de Groot 2009[18] EU/Mexico 9 mo (6 mo) Pulse Cyc 12 mo (6 mo) 15 mo (6 mo) 18 mo (6 mo) Relapse 72 (76) 66 (76) 63 (76) 62 (76) 62 (76) 62 (76) 65 (73) 60 (73) 58 (73) 55 (73) 54 (73) 54 (73) SCr 225 mol/l/ SCr 2.55 mg/dl GFR 38 ml/min/1.73 m2 49 (68%) [43 (66%)] 61 (92%) [55 (92%)] 61 (97%) [58 (100%)] nd 61 (98%) [55 (100%)] 61 (98%) [54 (100%)] 61 (98%) [54 (100%)] RR 1.03 (0.81-1.30)
259
18 mo (6 mo)
Pulse Cyc
76 (76)
73 (73)
nd
5 (7%) [1 (1%)]
RR 4.80 (0.57-40.13)
258
NS (0.105)
Fair
nd nd nd nd nd nd
RR 1.01 (0.91-1.12)
260
Remission
RR 0.98 (0.95-1.02)
263
RR 0.98 (0.95-1.02)
264
Calculated by ERT Calculated by ERT 259 Calculated by ERT 260 Calculated by ERT 261 Calculated by ERT 262 Calculated by ERT 263 Calculated by ERT 264 Calculated by ERT
257 258
Relapse
de Groot EU/Mexico
20091
>9 mo (6 mo)
Pulse Cyc
76 (76)
73 (73)
nd
13 (17%) [6 (8%)
nd
Fair
Adverse events Any adverse event Leukopen ia Infection Serious/ lifethreatenin g infection Alopecia Cancer Hemorrha gic cystitis Amenorrh ea de Groot 2009[18] EU/Mexico SCr 225 mol/l/ SCr 2.55 mg/dl GFR 38 ml/min/1.73 m2
58 (77%) [56 (77%)] 20 (26%) [33 (45%)] 20 (26%) [21 (29%)] 9 mo (6 mo) Daily p.o. Cyc 76 (76) 73 (73) 7 (9%) [10 (14%)] 0 (0%) [2 (3%)] 1 (1%) [1 (0%)] 2 (3%) [1 (1%)] 1 (1%) [0 (0%)]
RR 0.99 (0.83-1.19)
265
nd 0.016 nd
RR 0.58 (0.37-0.92)
266
Pulse Cyc
nd
nd
Fair
nd nd nd nd
--
Calculated by ERT Calculated by ERT 267 Calculated by ERT 268 Calculated by ERT
265 266
Supplementary table 99. Summary table of RCT examining induction with pulse Cyc vs. daily p.o. Cyc in patients with ANCA vasculitis (continuous outcomes)
Outcome Study, Year Country Duration Outcome measurement (Treatment) 9 mo (6 mo) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) 32 (29) Intervention (Control) 5 (8) P value Quality
Pulse Cyc
76 (76)
73 (73)
nd
ml/min/ 1.73 m2
NS (0.36)
Fair
Supplementary table 100. Evidence profile of RCTS examining induction with rituximab vs. Cyc in patients with ANCA vasculitis
Outcome # of studies and study design 2 RCTs (High) 0 RCT 2 RCTs (High) 1 RCT (High) 0 RCT 0 RCT 0 RCT 2 RCTs (High) 2 RCTs (High) Total N (treatment) 241 (132) -241 (132) 44 (33) ---241 (132) 241 (132) Methodological quality of studies per outcome Some limitations (-1) -Some limitations (-1) No limitations (0) ---Some limitations (-1) Consistency across studies No important inconsistencies (0) -No important inconsistencies (0) N/A ---No important inconsistencies (0) Directness of the evidence generalizability/ applicability Direct (0) -Direct (0) Direct (0) ---Direct (0) Summary of findings Other considerations Quality of evidence for outcome None -None Sparse (-1) ---None Moderate -Moderate Moderate ---Moderate Qualitative and quantitative description of effect No difference -No difference No difference ---No difference No difference Importance of outcome Critical Critical High High High High Moderate Moderate Moderate
Mortality ESRD Remission Relapse Proteinuria (categorical) Kidney function (categorical) Proteinuria (continuous) Kidney function (continuous) Adverse events
Supplementary table 101. Summary table of RCTs examining induction with rituximab vs. Cyc in patients with ANCA vasculitis (categorical outcomes)
Outcome Mortality Death Jones 2010[43] EU & Australia Stone 2010[75] Multi Jones 2010[43] EU & Australia 12 mo (6 mo for rituximab; 12 mo for Cyc) 6 mo (6 mo) 12 mo (6 mo for rituximab; 12 mo for Cyc) Rituximab + i.v. Cyc i.v. rituximab + placebo Cyc i.v. Cyc followed by AZA Cyc + placeborituximab i.v. Cyc followed by AZA 33 (33) 99 (99) 11 (11) 98 (98) GFR 20 ml/min/1.73 m2 eCrCl 54 ml/min nd 6 (18%) [2 (18%)] 1 (1%) [2 (2%)] RR 1.00269 (0.24-4.25) RR 0.49 (0.05-5.37) NS (1.00) nd Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Results Events (%) Intervention RR/OR/HR [Control] P value Quality
Death Remission Sustained remission Remission ANCA negative Proteinase 3ANCA negative Myeloperoxida se-ANCA negative Relapse Relapse Adverse events Leukopenia All infections
nd
Fair
33 (33)
11 (11)
GFR 20 ml/min/1.73 m2
nd
6 mo (6 mo)
Cyc + placeborituximab
99 (99)
98 (98)
eCrCl 54 ml/min
nd
33 (33)
11 (11)
GFR 20 ml/min/1.73 m2
nd
4 (27%) [1 (10%)]
RR 1.33271 (0.17-10.70)
NS (0.70)
Good
33 (33)
11 (11)
GFR 20 ml/min/1.73 m2
nd
nd Good nd
Calculated by ERT Calculated by ERT 271 Calculated by ERT 272 Calculated by ERT 273 Calculated by ERT
269 270
Serious infection All infusion reactions Cancer Events requiring hospitalization or lifethreatening Cancer Leukopenia Thrombocytop enia Infection Hemorrhagic cystitis Hospitalization due to disease or treatment Infusion reaction preventing further infusions of investigational medication All AEs All serious AEs
6 (18%) [2 (18%)] 2 (6%) [0 (0%)] 2(6%) [0 (0%)] 12 (36%) [4 (36%)] 1 (1%) [1 (1%)] 3 (3%) [10 (10%)] 3 (3%) [1 (1%)] 7 (7%) [7 (7%)] 1 (1%) [1 (1%)] Stone 2010[75] Multi 6 mo (6 mo) i.v. rituximab + placebo Cyc Cyc + placeborituximab 99 (99) 98 (98) eCrCl 54 ml/min nd 8 (8%) [2 (2%)]
RR 1.00274 (0.24-4.25) --RR 1.00275 (0.41-2.47) RR 0.99276 (0.06-15.61) RR 0.30277 (0.08-1.05) RR 2.97278 (0.31-28.06) RR 0.99279 (0.36-2.72) RR 0.99280 (0.06-15.61) RR 3.96281 (0.86-18.18)
nd nd nd
nd
nd nd nd nd nd nd
1 (1%) [0 (0%)]
--
nd
Fair
---
nd nd
Fair Fair
Calculated by ERT Calculated by ERT 276 Calculated by ERT 277 Calculated by ERT 278 Calculated by ERT 279 Calculated by ERT 280 Calculated by ERT 281 Calculated by ERT
274 275
Supplementary table 102. Summary table of RCTs examining induction with rituxamib vs. Cyc in patients with ANCA vasculitis (continuous outcomes)
Outcome SCr/GFR/CrCl Median eGFR eCrCl Jones 2010[43] EU & Australia Stone 2010[75] Multi 12 mo (6 mo for rituxamib; 12 mo for Cyc) 6 mo (6 mo) Rituximab + i.v. Cyc i.v. rituximab + placebo Cyc i.v. Cyc followed by AZA Cyc + placeborituximab 33 (33) 99 (99) 11 (11) 98 (98) GFR 20 ml/min/ 1.73 m2 eCrCl 54 ml/min nd ml/min/1 .73 m2 ml/min 20 (12) 54 (69) 29 (27) +11.2 (+10.5) NS (0.14) nd Good Study, Year Country Duration Outcome measurement (Treatment) Description Intervention Control No. Analyzed (Enrolled) Intervention Control GFR/SCr Proteinuria Units Results Baseline Intervention (Control) Intervention (Control) P value Quality
nd
Fair
References 1. Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome. Report of the International study of Kidney Disease in Children. Lancet 2(7878):423-7, 1974 2. Alexopoulos E: Treatment of severe IgA nephropathy with omega-3 fatty acids: the effect of a "very low dose" regimen. Renal failure 26(4):453-9, 2004 3. Appel GB, Contreras G, Dooley MA et al.: Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Journal of the American Society of Nephrology 20(5):1103-12, 2009 4. Austin HA I, Illei GG, Braun MJ, Balow JE: Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. Journal of the American Society of Nephrology 20(4):901-11, 2009 5. Bagga A: Enalapril dosage in steroid-resistant nephrotic syndrome. Pediatric nephrology 19(1):45-50, 2004 6. Ballardie FW, Roberts IS: Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. Journal of the American Society of Nephrology 13(1):142-8, 2002 7. Bennett WM, Walker RG, Kincaid-Smith P: Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial. Clinical Nephrology 31(3):128-31, 1989 8. Bircan Z, Kara B: Intravenous cyclophosphamide is the drug of choice for steroid dependent nephrotic syndrome. Pediatrics International 45(1):65-7, 2003 9. Chan MK, Kwan SY, Chan KW, Yeung CK: Controlled trial of antiplatelet agents in mesangial IgA glomerulonephritis. American Journal of Kidney Diseases 9(5):417-21, 1987 10. Chan TM, Li FK, Tang CS et al.: Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group. New England Journal of Medicine 343(16):1156-62, 2000 11. Chan TM, Lin AW, Tang SC et al.: Prospective controlled study on mycophenolate mofetil and prednisolone in the treatment of membranous nephropathy with nephrotic syndrome. Nephrology 12(6):576-81, 2007 12. Chan TM, Tse KC, Tang CS et al.: Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. Journal of the American Society of Nephrology 16(4):1076-84, 2005 13. Chen X: Effects of co-administration of urokinase and benazepril on severe IgA nephropathy. Nephrology Dialysis Transplantation 19(4):852-57, 2004 14. Choudhry S, Bagga A, Hari P et al.: Efficacy and safety of tacrolimus versus cyclosporine in children with steroidresistant nephrotic syndrome: a randomized controlled trial. American Journal of Kidney Diseases 53(5):760-9, 2009 15. Contreras G, Pardo V, Leclercq B et al.: Sequential therapies for proliferative lupus nephritis. New England Journal of Medicine 350(10):971-80, 2004 16. Contreras G, Tozman E, Nahar N, Metz D: Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus 14 Suppl 1:s33-8, 2005
17. Coppo R: IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria. Journal of the American Society of Nephrology 18(6):1880-8, 2007 18. de Groot K, Harper L, Jayne DR et al.: Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Annals of Internal Medicine 150(10):670-80, 2009 19. Donadio JV, Anderson CF, Mitchell JC et al.: Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy. The New England Journal of Medicine 310(22):1421-6, 1984 20. Donadio JV, Bergstralh EJ, Offord KP et al.: A controlled trial of fish oil in IgA nephropathy. The New England Journal of Medicine 331(18):1194-9, 1994 21. Dorresteijn EM, Kist-van Holthe JE, Levtchenko EN et al.: Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome. Pediatric Nephrology 23(11):2013-20, 2008 22. Dussol B, Morange S, Burtey S et al.: Mycophenolate mofetil monotherapy in membranous nephropathy: a 1-year randomized controlled trial. American Journal of Kidney Diseases 52(4):699-705, 2008 23. Eguchi A: Combined cyclosporine and prednisolone therapy in adult patients with the first relapse of minimalchange nephrotic syndrome. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 25(1):124-9, 2010 24. El-Shafey EM, Abdou SH, Shareef MM: Is mycophenolate mofetil superior to pulse intravenous cyclophosphamide for induction therapy of proliferative lupus nephritis in Egyptian patients? Clinical & Experimental Nephrology 14(3):214-21, 2010 25. Ferraro PM, Ferraccioli GF, Gambaro G et al.: Combined treatment with renin-angiotensin system blockers and polyunsaturated fatty acids in proteinuric IgA nephropathy: a randomized controlled trial. Nephrology Dialysis Transplantation 24(1):156-60, 2009 26. Flanc RS, Roberts MA, Strippoli GF et al.: Treatment for lupus nephritis. Cochrane Database of Systematic Reviews (1):CD002922, 2004 27. Frasca GM, Martello M: Defibrotide treatment and disease progression in patients with IgA nephropathy and impaired renal function at diagnosis. Clinical Drug Investigation 13(4):185-91, 1997 28. Frisch G, Lin J, Rosenstock J et al.: Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrology Dialysis Transplantation 20(10):2139-45, 2005 29. Ginzler EM, Dooley EM, Aranow C: Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. The New England Journal of Medicine 353(21):2219-28, 2005 30. Grootscholten C: Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial. Kidney International 70(4):732-42, 2006 31. Hafeez F, Ahmad TM, Anwar S: Efficacy of steroids, cyclosporin and cyclophos-phamide in steroid resistant idiopathic nephrotic syndrome. Journal of the College of Physicians & Surgeons 15(6):329-32, 2005 32. Harmankaya O: Efficacy of immunosuppressive therapy in IgA nephropathy presenting with isolated hematuria. International Urology & Nephrology 33(1):167-71, 2002
33. Hodson EM, Habashy D, Craig JC: Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews (2):CD003594, 2006 34. Hodson EM, Willis NS, Craig JC: Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database of Systematic Reviews (1):CD002290, 2008 35. Hogg RJ, Lee J: Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group. Clinical Journal of the American Society of Nephrology: CJASN 1(3):467-74, 2006 36. Horita Y: Prednisolone co-administered with losartan confers renoprotection in patients with IgA nephropathy. Renal Failure 29(4):441-6, 2007 37. Houssiau FA, D'Cruz D, Sangle S et al.: Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Annals of the Rheumatic Diseases 69(12):2083-9, 2010 38. Houssiau FA, Vasconcelos C: Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis and Rheumatism 46(8):2121-31, 2002 39. Houssiau FA, Vasconcelos C, D'Cruz D et al.: The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide. Annals of the rheumatic diseases 69(1):61-4, 2010 40. Hu W: Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis. Chinese Medical Journal 115(5):705-9, 2002 41. Ishikura K, Ikeda M, Hattori S et al.: Effective and safe treatment with cyclosporine in nephrotic children: a prospective, randomized multicenter trial. Kidney International 73(10):1167-73, 2008 42. Jha V: A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy. Journal of the American Society of Nephrology 18(6):1899-904, 2007 43. Jones RB TJH: Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. The New England journal of medicine 363(3):211-20, 2010 44. Julian BA, Barker C: Alternate-day prednisone therapy in IgA nephropathy. Preliminary analysis of a prospective, randomized, controlled trial. Contributions to Nephrology 104:198-206, 1993 45. Kano K: Effect of fluvastatin and dipyridamole on proteinuria and renal function in childhood IgA nephropathy with mild histological findings and moderate proteinuria. Clinical Nephrology 60(2):85-9, 2003 46. Katafuchi R: Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy. American Journal of Kidney Diseases 41(5):972-83, 2003 47. Koike M, Takei T, Uchida K et al.: Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center. Clinical & Experimental Nephrology 12(4):250-5, 2008 48. Lai KN, Lai FM, Ho CP, Chan KW: Corticosteroid therapy in IgA nephropathy with nephrotic syndrome: a longterm controlled trial. Clinical Nephrology 26(4):174-80, 1986
49. Li EK, Tam LS, Zhu TY et al.: Is combination rituximab with cyclophosphamide better than rituximab alone in the treatment of lupus nephritis? Rheumatology 48(8):892-8, 2009 50. Li PK, Leung CB, Chow KM et al.: Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. American Journal of Kidney Diseases 47(5):751-60, 2006 51. Lv J, Zhang H, Chen Y et al.: Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. American Journal of Kidney Diseases 53(1):26-32, 2009 52. Maes BD, Oyen R: Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study. Kidney International 65(5):1842-9, 2004 53. Manno C, Torres DD, Rossini M et al.: Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy. Nephrology Dialysis Transplantation 24(12):3694-701, 2009 54. Mantan M, Sriram CS, Hari P et al.: Efficacy of intravenous pulse cyclophosphamide treatment versus combination of intravenous dexamethasone and oral cyclophosphamide treatment in steroid-resistant nephrotic syndrome. Pediatric Nephrology 23(9):1495-502, 2008 55. Martinelli R: Cyclophosphamide in the treatment of focal segmental glomerulosclerosis. Brazilian Journal of Medical & Biological Research 37(9):1365-1372, 2004 56. Miyasaka N, Kawai S, Hashimoto H: Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Modern Rheumatology 19(6):606-15, 2009 57. Moroni G: A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years. Clinical Journal of the American Society of Nephrology: CJASN 1(5):925-32, 2006 58. Mota-Hernandez F: Prednisone versus placebo in membranoproliferative glomerulonephritis: long-term clinicopathological correlations. The International Journal of Pediatric Nephrology 6(1):25-8-Mar, 1985 59. Nayagam SL, Ganguli A, Rathi M et al.: Mycophenolate mofetil or standard therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study. Nephrology Dialysis Transplantation 23(6):1926-30, 2008 60. Ong LM, Hooi LS, Lim TO et al.: Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology 10(5):504-10, 2005 61. Pettersson EE, Rekola S, Berglund L: Treatment of IgA nephropathy with omega-3-polyunsaturated fatty acids: a prospective, double-blind, randomized study. Clinical Nephrology 41(4):183-90, 1994 62. Plank C, Kalb V, Hinkes B et al.: Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft fur Padiatrische Nephrologie. Pediatric Nephrology 23(9):1483-93, 2008 63. Ponticelli C: A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy. Kidney International 48(5):1600-4, 1995 64. Ponticelli C: A randomized pilot trial comparing methylprednisolone plus a cytotoxic agent versus synthetic adrenocorticotropic hormone in idiopathic membranous nephropathy. American Journal of Kidney Diseases 47(2):233-40, 2006
65. Pozzi C: Corticosteroids in IgA nephropathy: a randomised controlled trial. Lancet 353(9156):883-7, 1999 66. Pozzi C: Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial. Journal of the American Society of Nephrology 15(1):157-63, 2004 67. Pozzi C, Andrulli S, Pani A et al.: Addition of azathioprine to corticosteroids does not benefit patients with IgA nephropathy. Journal of the American Society of Nephrology 21(10):1783-90, 2010 68. Praga M: Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial. Journal of the American Society of Nephrology 14(6):1578-83, 2003 69. Praga M: Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney International 71(9):924-30, 2007 70. Samuels JA, Strippoli GF, Craig JC et al.: Immunosuppressive treatments for immunoglobulin A nephropathy: a meta-analysis of randomized controlled trials. Nephrology 9(4):177-85, 2004 71. Schieppati A, Perna A, Zamora J et al.: Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database of Systematic Reviews (4):CD004293, 2004 72. Shi X: [The effects of angiotensin-converting enzyme inhibitor on IgA nephropathy and the influencing factors]. Zhonghua nei ke za zhi [Chinese journal of internal medicine] 41(6):399-403, 2002 73. Shimizu A: Low-dose losartan therapy reduces proteinuria in normotensive patients with immunoglobulin A nephropathy. Hypertension Research 31(9):1711-17, 2008 74. Sobh MA, Moustafa FE, Sally SM et al.: A prospective, randomized therapeutic trial for schistosomal specific nephropathy. Kidney International 36(5):904-7, 1989 75. Stone JH, Merkel PA, Spiera R et al.: Rituximab versus cyclophosphamide for ANCA-associated vasculitis. New England Journal of Medicine 363(3):221-32, 2010 76. Strippoli GF, Manno C, Schena FP: An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism. American Journal of Kidney Diseases 41(6):1129-39, 2003 77. Szeto CC, Kwan BC, Lai FM et al.: Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatology 47(11):1678-81, 2008 78. Taji Y, Kuwahara T, Shikata S, Morimoto T: Meta-analysis of antiplatelet therapy for IgA nephropathy. Clinical & Experimental Nephrology 10(4):268-73, 2006 79. Tang S, Leung JC, Chan LY et al.: Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy. Kidney International 68(2):802-12, 2005 80. Tang SC, Tang AW, Wong SS et al.: Long-term study of mycophenolate mofetil treatment in IgA nephropathy. Kidney International 77(6):543-9, 2010 81. Tarshish P: Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone--a report of the International Study of Kidney Disease in Children. Pediatric Nephrology 6(2):123-30, 1992 82. Tarshish P: Cyclophosphamide does not benefit patients with focal segmental glomerulosclerosis. A report of the International Study of Kidney Disease in Children. Pediatric Nephrology 10(5):590-3, 1996
83. Walker RG, Yu SH, Owen JE, Kincaid-Smith P: The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial. Clinical Nephrology 34(3):103-7, 1990 84. Walters G, Willis NS, Craig JC: Interventions for renal vasculitis in adults. Cochrane Database of Systematic Reviews (3):CD003232, 2008 85. Wang J: Induction therapies for class IV lupus nephritis with non-inflammatory necrotizing vasculopathy: mycophenolate mofetil or intravenous cyclophosphamide. Lupus 16(9):707-12, 2007 86. Xu G, Tu W, Jiang D, Xu C: Mycophenolate mofetil treatment for IgA nephropathy: a meta-analysis. American Journal of Nephrology 29(5):362-7, 2009 87. Yee CS, Gordon C: EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Annals of the Rheumatic Diseases 63(5):525-9, 2004 88. Yi Z: Effect of fosinopril in children with steroid-resistant idiopathic nephrotic syndrome. Pediatric Nephrology 21(7):967-72, 2006 89. Yoshikawa N: A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. Journal of the American Society of Nephrology 10(1):101-9, 1999 90. Yoshikawa N: Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial. Clinical Journal of the American Society of Nephrology: CJASN 1(3):511-7, 2006 91. Yoshikawa N, Japanese Pediatric IgA Nephropathy Treatment Study Group: [A prospective controlled study of sairei-to in childhood IgA nephropathy with focal/minimal mesangial proliferation.]. Nippon Jinzo Gakkai Shi 39(5):503-6, 1997 92. Zauner I, Collaborative Glomerulonephritis Therapy Study Group (CGTS): Effect of aspirin and dipyridamole on proteinuria in idiopathic membranoproliferative glomerulonephritis: a multicentre prospective clinical trial. Nephrology Dialysis Transplantation 9(6):619-22, 1994 93. Zimmerman SW, Moorthy AV, Dreher WH, Friedman A: Prospective trial of warfarin and dipyridamole in patients with membranoproliferative glomerulonephritis. The American Journal of Medicine 75(6):920-7, 1983